Benzenesulphonamide derivatives, method for production and use thereof for treatment of pain

ABSTRACT

The present invention concerns novel benzenesulphonamide compounds, defined by formula I. 
                         
Therapeutic compositions comprising the benzenesulphonamide compounds of the invention or salts thereof and methods for producing the benzenesulphonamide compounds of the invention are also disclosed. The benzenesulphonamide compounds of the invention or salts thereof are useful for treating pain, such as hyperalgesia and major algesia.

The present invention concerns novel compounds of benzenesulphonamidetype, their method of preparation and their use to obtain pharmaceuticalcompositions.

These novel compounds may be given therapeutic use, in particular totreat pain.

PRIOR ART

Compounds are already known whose structure includes a group ofbenzenesulphonamide type. For example, through EP 236 163 and EP 236164, N-α-arylsulphonylaminoacyl-p-amidino-phenyl-alaninamide derivativesmay be cited which are selective thrombin inhibitors and can be used asanti-thrombotics. Also, from EP 614 911, compounds are known having afairly close structure to the preceding compounds, simultaneouslycontaining an arylsulphamoyl group and a substituted phenylamidinegroup, which have the property of binding to receptors of the Yneuropeptide and can be used to treat hypertension, angina pectoris,atherosclerosis, depression, anxiety, inflammation, allergy or excessfat.

EP 558 961 also suggests the use of arylsulphonamide-type compounds ofsubstituted amino acids for the treatment of thrombosis on account oftheir anticoagulant properties.

Studies on the anti-thrombotic properties of compounds containing anarylsulphonamide group in their structure and a phenylamidine group havealso been published in Pharmazie 1984 vol. 39 (5) pages 315-317 andPharmazie 1986 vol. 41 (4) p 233-235.

In the same field of pharmacological activity WO 92/16549 A1 describesderivatives of phenylalanine comprising an arylsulphonamide group, whichare proteinase inhibitors, in particular thrombin inhibitors.

Also, according to WO 97/25315, compounds are known havingN-(arylsulphonyl)amino-acid structure, which can be used to treatinflammatory diseases.

Among the prior art documents proposing structural elements ofarylsulphonamide type, mention may be made of WO 96/40639, WO 97/24349,WO 98/03503, WO 98/24783 and WO 99/00387, pertaining to antagonistcompounds of the B2 receptor of bradykinin. Antagonist compounds of theB₁ receptor of bradykinin, whether peptide or non-peptide, are alsoknown through documents WO 01/05783, WO 02/099388 and WO 97/09346.

OBJECT OF THE INVENTION

The invention concerns novel compounds comprising the substitutedbenzenesulphonamide chain, said compounds being notably useful as activeingredients in medicinal products intended to treat pain, in particularhyperalgesia and major algesia.

DESCRIPTION

According to the present invention, as novel industrial product acompound is proposed of benzenesulphonamide type, characterized in thatit is selected from the group consisting of:

a) compounds of formula:

in which

-   -   R₁, R₂, R₃, R₄ each independently represent one or more atoms or        groups of atoms selected from a hydrogen atom, halogens, C₁-C₃        alkyl groups, C₁-C₃ alkoxy groups, CF₃ or OCF₃ groups,    -   R_(a) represents a C₁-C₄ alkyl group,    -   Y represents a saturated C₂-C₅ alkylene group, optionally        interrupted by an oxygen atom, an unsaturated C₂-C₄ alkylene        group, or a —CH₂—CO—NH—CH₂— group,    -   X represents CH or a nitrogen atom,    -   p represents 2 or 3,    -   A represents a single bond, a nitrogen atom optionally        substituted with a methyl group, or a straight or branched C₁-C₅        alkylene group, optionally hydroxylated or of which one of the        carbon atoms is oxidized into a ketone function, provided that A        and X together do not represent a nitrogen atom,    -   B represents a nitrogen-containing heterocycle or an amine group        optionally substituted with one or two C₁-C₄ alkyl groups,

b) the addition salts of the above formula I compounds with an acid.

The invention, when the formula I compounds comprise a centre ofassymetry, also concerns each of the optical isomers either pure ormixed, and their respective salts or salt mixtures.

According to the invention, a method is also proposed to prepare formulaI compounds and their addition salts.

The use is also put forward of a substance selected from the formula Icompounds and their non-toxic addition salts for the preparation of amedicinal product which can be used in human or animal therapy intendedfor the prevention or treatment of pain-related pathologies, inparticular hyperalgesia subsequent to an inflammatory condition, ormajor algesia connected with other pathological conditions such ascancer for example.

DETAILED DESCRIPTION

In formula I, by alkyl group is meant a straight, branched or cyclizedhydrocarbon chain. A C₁-C₃ alkyl group is notably a methyl, ethyl,propyl, cyclopropyl or 1-methyl-ethyl group. A C₁-C₄ alkyl group, inaddition to the above-cited examples, will notably comprise butyl,1-methylpropyl and 1,1-dimethylethyl groups.

By C₁-C₃ alkoxy group is meant an OR group in which R is a C₁-C₃ alkylgroup, the term alkyl having the meaning given above. Said group is forexample a methoxy, ethoxy, propoxy or 1-methylethoxy group.

By saturated C₂-C₅ alkylene group is meant a —(CH₂)_(n)— group in whichn is 2, 3, 4 or 5 if it is a straight group or, for example a—CH(CH₃)—CH₂—CH₂— or —C(CH₃)₂—CH₂— group if it is a branched group. Byan alkylene group interrupted by an oxygen atom is meant for example thegroups —CH₂—CH₂—O—CH₂—, —CH₂—O—CH₂—CH₂— or even —CH₂—CH₂—O—CH₂—CH₂—.

By unsaturated C₂-C₄ alkylene group, is meant a group comprising 2 to 4carbon atoms of which 2 consecutive atoms are bound by an ethylene bond,for example the groups —CH₂—CH═CH—CH₂—, —CH═CH—CH₂—, —CH═C(CH₃)—CH₂—,CH₂—CH═CH— or —CH═CH—CH(CH₃)—.

By halogen is meant an atom of fluorine, chlorine or bromine andpreferably a fluorine or chlorine atom.

By alkylamino or dialkylamino groups is meant the NH(R) or N(R)₂ groupsin which R is a C₁-C₄ alkyl group, the term alkyl having the meaninggiven above.

By nitrogen-containing heterocycle is notably meant the azetidine,pyrrolidine, morpholine, piperidine, piperazine,N-(C₁-C₄)alkylpiperidine, N-(C₁-C₄)alkylpiperazine, quinuclidine,tropane, N-(C₁-C₄)alkylhomopiperazine, aminopyridine andN-(C₁-C₄)alkylimidazole rings.

By addition salts is meant the addition salts obtained by reaction of aformula I compound containing at least one basic function in itsnon-salified form, with a mineral or organic acid. Preferably, these arepharmaceutically acceptable addition salts.

Among the mineral acids suitable for salifying a basic compound offormula I, preference is given to hydrochloric, hydrobromic, phosphoricand sulphuric acids. Among the organic acids suitable for salifying abasic compound of formula 1, preference is given to methanesulphonic,benzenesulphonic, toluenesulphonic, maleic, fumaric, oxalic, citric,tartaric, lactic and trifluoroacetic acids.

Among the formula I compounds, preference is given to those which meetat least one of the following conditions:

-   -   R₁ represents hydrogen, a halogen, a C₁-C₃ alkyl group or C₁-C₃        alkoxy group;    -   R₂ represents a halogen, a C₁-C₃ alkyl group or CF₃ group;    -   R₃ represents hydrogen, a halogen, a C₁-C₃ alkyl group or C₁-C₃        alkoxy group;    -   R₄ represents hydrogen or a C₁-C₃ alkyl group;    -   R_(a) represents a methyl group;    -   Y represents a saturated C₂-C₅ alkylene group, optionally        interrupted by an oxygen atom;    -   p represents 2;    -   A represents a single bond or a straight or branched C₁-C₅        alklene group;    -   B represents an azetidinyl, pyrrolidinyl, morpholinyl,        piperidinyl, piperazinyl, N-(C₁-C₄)alkylpiperidinyl,        N-(C₁-C₄)alkylpiperazinyl, quinuclidinyl, tropanyl or        N-(C₁-C₄)alkylhomopiperazinyl group.

Particular preference is given to formula I compounds which meet atleast one of the following conditions:

-   -   R₁ represents a C₁-C₃ alkoxy group;    -   R₂ and R₃ each represent a C₁-C₃ alkyl group, preferably a        methyl group at position 2,6 on the aromatic ring;    -   R₄ represents hydrogen;    -   Y represents a C₃-C₅ alkylene group interrupted by an oxygen        atom, preferably a —CH₂—CH₂—O—CH₂— group;    -   B represents a piperidinyl, N-(C₁-C₄)alkylpiperidinyl, or        N-(C₁-C₄) alkylpiperazinyl group.

Preference is also given to compounds of formula Ia:

in which

-   -   R₁represent one atom or group of atoms selected from a hydrogen        atom, halogens, C₁-C₃ alkyl groups, C₁-C₃ alkoxy groups, CF₃ or        OCF₃ groups,    -   R₂ represents one atom or group of atoms selected from a        hydrogen atom, halogens, C₁-C₃ alkyl groups, C₁-C₃ alkoxy        groups, CF₃ or OCF₃ groups,    -   R₃ represents one atom or group of atoms selected from a        hydrogen atom, halogens, C₁-C₃ alkyl groups, C₁-C₃ alkoxy        groups, CF₃ or OCF₃ groups    -   Y represents a saturated C₂-C₅ alkylene group, optionally        interrupted by an oxygen atom, an unsaturated C₂-C₄ alkylene        group or a —CH₂—CO—NH—CH₂— group,    -   A represents a single bond or a —(CH₂)_(m)— group,    -   R represents a saturated nitrogen-containing heterocycle,        notably selected from the pyrrolidine, morpholine, piperidine,        quinuclidine, tropane rings, or a tertiary amine group, notably        a dialkylamino group,    -   m and p each independently represent 2 or 3.

Preference is also given to compounds of formula Ib:

in which

-   -   R₁, R₂, R₃ each independently represent one or more atoms or        groups of atoms selected from a hydrogen atom, halogens, C₁-C₃        alkyl groups, C₁-C₃ alkoxy groups, CF₃ or OCF₃ groups,    -   Y represents a saturated C₂-C₅ alkylene group, optionally        interrupted by an oxygen atom, an unsaturated C₂-C₄ alkylene        group, or a —CH₂—CO—NH—CH₂— group,    -   A represents a single bond or a saturated C₁-C₅ alkylene group,        optionally hydroxylated,    -   R represents a saturated nitrogen-containing heterocycle notably        selected from the N-methylpiperazine, N-methylpiperidine rings,        or a tertiary amine group, notably a dialkylamino group.

According to the invention, a general method is put forth for preparingformula I compounds or their addition salts, comprising the stepsconsisting of:

a) allowing an acid of formula:

in which

-   R₁, R₂, R₃, R₄ each independently represent one or more atoms or    groups of atoms selected from a hydrogen atom, halogens, C₁-C₃ alkyl    groups, C₁-C₃ alkoxy groups, CF₃ or OCF₃ groups,-   R_(a) represents a C₁-C₄ alkyl group,-   Y represents a saturated C₂-C₅ alkylene group, optionally    interrupted by an oxygen atom, an unsaturated C₂-C₄ alkylene group,    or a —CH₂—CO—NH—CH₂— group,    to react with a nitrogen-containing heterocycle of formula:

in which

-   X represents CH or a nitrogen atom,-   p represents 2 or 3,-   A represents a single bond, a nitrogen atom optionally substituted    with a methyl group (if X does not also represent a nitrogen atom),    or a straight or branched C₁-C₅ alkylene group, optionally    hydroxylated or of which one of the carbon atoms is oxidized into a    ketone function,-   B represents a nitrogen-containing heterocycle or an amine group    optionally substituted with one or two C₁-C₄ alkyl groups, on the    understanding that if a non-substituted nitrogen atom is present,    this nitrogen atom is protected by an amino-protecting group such as    a Boc group (1,1-dimethylethoxycarbonyl) or Cbz group    (phenylmethoxycarbonyl) for example, in a solvent such as    tetrahydrofuran, dichloromethane or dimethylformamide for example,    in the presence of activators such as EDCI    (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), DIC    (diisopropylcarbodiimide) or HOAT (1-hydroxy-7-azabenzotriazole), at    a temperature generally lying between ambient temperature and the    boiling point of the solvent, for approximately 2 to 15 hours, to    obtain the amide of formula:

in which R₁, R₂, R₃, R₄, R_(a), Y, p, X, A and B maintain the samemeaning as in the starting products,

b) if necessary, removing the amino-protecting groups, for examplethrough the action of trifluoroacetic acid in the presence of anisole ifsaid amino-protecting group is a Boc group, or by catalytichydrogenation if the protecting group is a Cbz group,

c) if necessary, obtaining an addition salt of the formula I compoundwith a mineral or organic acid, following usual procedures known topersons skilled in the art.

This general method for preparing an amide function starting with acarboxylic acid and an amine may be modified to use activatorsimmobilized on an insoluble resin, for example resins having apolystyrene skeleton supporting carbodiimide functions.

As a variant of the above-described general method, the acid of formulaII may be converted intermediately into an acid chloride of formula IIa,

notably through the action of a chlorinating agent such as oxalylchloride or thionyl chloride, said acid chloride then being allowed toreact with the nitrogen-containing heterocycle of formula III using aconventional reaction conducted in a solvent and preferably in thepresence of an aprotic organic base such as triethylamine or pyridinefor example, to obtain the compound of formula I.

The acids of formula II in which Y represents a —CH₂—CH₂—O—CH₂— groupmay be prepared following a method consisting of:

a) allowing a benzenesulphonyl chloride of formula:

in which R₁, R₂, R₃ and R₄ each independently represent a hydrogen orhalogen atom, a C₁-C₃ alkyl group, a C₁-C₃ alkoxy group, CF₃ or OCF₃group,to react with an aminoalcohol of formula:HN(R_(a))—CH₂—CH₂—OHin which R_(a) represents a C₁-C₄ alkyl group,

-   in a solvent such as dichloromethane for example, in the presence of    an aprotic organic base such as triethylamine or pyridine for    example, at a temperature lying between approximately 0 and 50° C.,    for approximately 1 to 3 hours, to obtain the sulphonamide of    formula:

in which R₁, R₂, R₃, R₄ and R_(a) remain unchanged,

b) allowing the compound of formula V obtained above to react with anester of bromacetic acid, preferably the t-butyl ester, in the presenceof a base such as sodium hydroxide for example and in a phase-transferpromoting medium containing quarternary ammonium salts, in a mixture ofsolvents such as water and toluene, at a temperature lying betweenapproximately 0° C. and 40° C. for approximately 1 to 5 hours, to obtainthe ester of formula:

c) hydrolysing the ester of formula VI, for example through the actionof trifluoroacetic acid, the reaction being conducted in a solvent suchas dichloromethane, at a temperature lying between approximately 0° C.and 50° C. for approximately 1 to 6 hours, to obtain the acid of formulaII:

in which R₁, R₂, R₃, R₄ and R_(a) remain unchanged and Y represents a—CH₂—CH₂—O—CH₂— group.

As a variant of the general method, the formula I compounds may beobtained by successively performing the steps consisting of:

a) allowing an acid compound of formula:

in which R_(a) represents a C₁-C₄ alkyl group,

-   Y represents a saturated C₂-C₅ alkylene group, optionally    interrupted by an oxygen atom, and Z_(a) represents an    amino-protecting group such as a benzyl group for example,    to react with a nitrogen-containing heterocycle of formula:

in which

-   X represents CH or a nitrogen atom,-   p represents 2 or 3,-   A represents a single bond, a nitrogen atom optionally substituted    with a methyl group (if X does not also represent a nitrogen atom),    or a straight or branched C₁-C₅ alkylene group optionally    hydroxylated or of which one of the carbon atoms is oxidized into a    ketone function,-   B represents a nitrogen-containing heterocycle or an amine group    optionally substituted with one or two C₁-C₄ alkyl groups, on the    understanding that, should a non-substituted nitrogen atom be    present, this nitrogen atom is protected by a different    amino-protecting group to the amino-protecting group used for acid    compound VII, such as a Boc group (1,1-dimethylethoxycarbonyl),    in a solvent such as tetrahydrofuran or dichloromethane or    dimethylformamide for example, in the presence of activators such as    EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), DIC    (diisopropylcarbodiimide) or HOAT (1-hydroxy-7-azabenzotriazole) for    example, at a temperature generally lying between ambient    temperature and the boiling point of the solvent, for approximately    2 to 15 hours, to obtain the amide of formula:

in which Z_(a), R_(a), Y, p, X, A and B maintain the same meaning as inthe starting compounds,

b) removing the Z_(a) amino-protecting group, for example by catalytichydrogenation if Z_(a) is a benzyl group, to obtain the secondary amineof formula:

in which R_(a), Y, p, X, A and B maintain the same meaning as in thepreceding compound,

c) allowing this secondary amine IX to react with a benzenesulphonylchloride of formula:

in which R₁, R₂, R₃ and R₄ each independently represent a hydrogen orhalogen atom, a C₁-C₃ alkyl group or a C₁-C₃ alkoxy group, CF₃ or OCF₃group, in a solvent such as dichloromethane for example, in the presenceof an aprotic organic base such as triethylamine or pyridine forexample, at a temperature lying between approximately 0 and 50° C., forapproximately 1 to 3 hours, to obtain the sulphonamide of formula:

in which R₁, R₂, R₃, R₄, R_(a), Y, p, X, A and B maintain the samemeaning as in the starting compounds,

d) if necessary, removing the amino-protecting groups, for examplethrough the action of trifluoroacetic acid in the presence of anisole ifsaid amino-protecting group is a Boc group,

e) if necessary, obtaining an addition salt of the formula I compoundwith a mineral or organic acid.

As a variant of the above method, step a) to form the amide bond may beconducted by first forming the acid chloride of formula VII, for examplethrough the action of oxalyl chloride or thionyl chloride in ananhydrous aprotic solvent, followed by reaction of the acid chlorideobtained with the formula III amine as described above, in a solvent andfor example in the presence of an aprotic base such as triethylamine.

The heterocyclic derivatives of formula III are known compounds,commercially available or described in the literature, or may beprepared using methods known to persons skilled in the art, for examplethrough a reductive amination reaction between piperazine orhomopiperazine and a ketone, for example in the presence of titaniumisopropoxide then a reaction with a reducing agent such as sodiumcyanoborohydride, or, if piperidine derivatives are used, throughcatalytic hydrogenation of pyridine-homologous compounds.

The invention will be more readily understood with the help of examplesof preparation of compounds and the results of pharmacological testsdemonstrating the therapeutic usefulness of these compounds. Theseexamples are non-limiting and cannot be interpreted as limiting thescope of the invention.

Among the abbreviations used in the description, M means mole, mM meansmillimole (10⁻³ mole). THF means tetrahydrofurane, DCM meansdichloromethane, DMF means dimethylformamide, TFA means trifluoroaceticacid. For compounds having a centre of assymetry, the absence of anyparticular indication means that the compound is in the form of theracemic mixture. In the spectral data for nuclear magnetic resonance,chemical shifts are indicated with reference to TMS (tetramethylsilane).

PREPARATION I N(2-hydroxyethyl)-4-methoxy-N,2,6-trimethylbenzene-sulphonamide

A solution of 1.76 g (23.4 mM) of 2-(methylamino)ethanol is prepared in100 ml of DCM and 5.4 g (53 mM) of triethylamine are added. The mixtureis cooled to 0° C. and a solution of 5 g (21.3 mM) of 2,6dimethyl-4-methoxybenzenesulphonyl chloride in 50 ml of DCM is addedprogressively. The mixture is then agitated for 3 hours at ambienttemperature, and then poured over 50 ml of 0.5 N hydrochloric acid. Theorganic phase is separated and then washed with water, dried overmagnesium sulphate and concentrated under reduced pressure. 5.8 g of thecompound sought after are thus obtained as a colourless oil(yield=100%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.70 (t, 1H); 3.80 (s, 3H); 3.48(q, 2H); 3.09 (t, 2H); 2.69 (s, 3H); 2.54 (s, 6H).

PREPARATION II[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]aceticacid, 1,1-dimethylethyl ester

A solution of 4.85 g (17.7 mM) of the compound obtained according topreparation I is prepared in 100 ml of toluene and 1.62 g oftetrabutylammonium chloride are added. The mixture is cooled to 0° C.and 100 ml of 35% sodium hydroxide are then added, then, progressively,3.95 ml (26.6 mM) of t-butyl bromacetate are added. The mixture isagitated at ambient temperature for 2 hours and the organic phase isthen separated by decanting, and washed with water to neutral pH andthen dried over sodium sulphate. After concentration under reducedpressure, an oil is obtained which is purified by silica gelchromatography in eluting with the aid of a cyclohexane/ethyl acetatemixture (75/25; v/v). 6.5 g of the compound sought after are thusobtained as a colourless oil (yield=94%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 3.89 (s, 2H); 3.80 (s, 3H); 3.56(t, 2H); 3.21 (t, 2H); 2.71 (s, 3H); 2.53 (s, 3H); 1.41 (s, 9H).

PREPARATION III[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]aceticacid

6.4 g (16.5 mM) of the ester obtained according to preparation II aredissolved in 80 ml of DCM, and 8 ml of trifluoroacetic acid are added.The mixture is agitated at ambient temperature for 4 hours, and thenconcentrated under reduced pressure. The residue from evaporation istaken up into solution in 100 ml of 1N sodium hydroxide and the solutionobtained is washed twice with 30 ml of ethyl acetate, and then acidifiedwith an N solution of hydrochloric acid and extracted with twice 80 mlof ethyl acetate. The organic phase is washed with water, dried oversodium sulphate and concentrated under pressure. The acid sought afteris thus obtained as an oil which crystallises (yield=95%).

M.Pt.=82° C.

EXAMPLE 11-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]acetyl]-4-[2-(1-pyrrolidinyl)ethyl]piperazine,bis-trifluoroacetate

482 mg cyclohexyldiimide grafted polystyrene resin are placed in 5 ml ofTHF for 20 minutes and 100 mg (0.31 mM) of the acid obtained accordingto preparation III in solution in 2 ml of THF, 37 mg (0.20 mM) of1-[2-(1-pyrrolidinyl)ethyl]piperazine and 2 mg of HOAT(1-hydroxy-7-azabenzotriazole), are then added. The mixture is agitatedfor 4 hours at ambient temperature and then filtered. The resin isrinsed with 4 ml of THF which is added to the filtrate. The filtrate isthen agitated with 50 mg of Amberlite IRA 400 resin (as OH⁻), for 3hours. After filtration, the resin is rinsed with 3 ml of THF which isadded to the filtrate. This filtrate is then treated with 100 mg ofisocyanate grafted polystyrene resin for 1 hour. The resin is separatedoff by filtration and the solution is concentrated under reducedpressure. The residue (63 mg) is purified by reverse phasechromatography on an X Terra Prep MS C18 column (eluent A: water+0.05%TFA, eluent B: acetonitrile+0.05% TFA, gradient: 10% B (t=0 to 2minutes) 60% B (t=2 to 17 minutes) 100% B (t=17 minutes to 18 minutes);flow rate=25 ml/mn; UV detection from 120 to 260 nm. The purifiedproduct is taken up into 1 ml of acetonitrile and it is mixed with 6 mlof a 1% solution of trifluoroacetic acid in water. The solution obtainedis then freeze-dried and 19 mg of the salt sought after are obtained asa yellow oil (yield=13%).

¹H NMR (300 MHz, CD₃CN) δ: 6.74 (s, 2H); 4.09 (s, 2H); 3.96 (s, 3H);3.70 (m, 1H); 3.59 (t, 2H); 3.48 (t, 2H); 3.33 (m, 5H); 3.19 (t, 2H);3.00 (m, 4H); 2.72 (s; 3H); 2.56 (s, 6H); 2.04 (m, 4H).

PREPARATION IV[2-[[(2,4,6-trimethylphenyl)sulphonyl]methylamino]ethoxy]-acetic acid,1,1-dimethylethyl ester

In operating analogously to preparation II, starting withN-(2-hydroxyethyl)-N,2,4,6-tetramethylbenzenesulphonamide, the estersought after is obtained as a beige oil (yield=98%).

¹H NMR (250 MHz, DMSO) δ: 7.06 (s, 2H); 4.01 (s, 2H); 3.58 (t, 2H); 3.25(t, 2H); 2.72 (s, 3H); 2.51 (s, 6H); 2.27 (s, 3H); 1.43 (s, 9H).

PREPARATION V[2-[[(2,4,6-trimethylphenyl)sulphonyl]methylamino]ethoxy]-acetic acid

In operating analogously to preparation III, starting with the compoundobtained according to preparation IV, the product sought after isobtained as a beige solid (yield=83%).

M.Pt.=58° C.

PREPARATION VI N-ethyl-N-(2-hydroxyethyl)-4-methoxy-2,6-dimethylbenzene-sulphonamide

In operating analogously to preparation I, starting with2-(ethylamino)ethanol, the product sought after is obtained as a yellowoil (yield=99%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.69 (t, 1H); 3.80 (s, 3H); 3.38(m, 2H); 3.14 (s, 2H).

PREPARATION VII[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]ethylamino]-ethoxy]aceticacid, 1,1-dimethylethyl ester

In operating analogously to preparation II, starting with the compoundobtained according to preparation VI, the product sought after isobtained as a colourless oil (yield=79%).

¹H NMR (250 MHz, DMSO) δ: 6.79 (s, 2H); 3.86 (s, 2H); 3.79 (s, 3H); 3.47(t, 2H); 3.24 (m, 4H); 2.53 (s, 6H); 1.40 (s, 9H); 1.00 (t, 3H).

PREPARATION VIII[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]ethylamino]-ethoxy]aceticacid

In operating analogously to preparation III, starting with the compoundobtained according to preparation VII, the product sought after isobtained as a white solid (yield=88%).

¹H NMR (250 MHz, DMSO) δ: 6.79 (s, 2H); 3.89 (s, 2H); 3.79 (s, 3H); 3.48(t, 2H); 3.24 (q, 2H); 3.21 (t, 2H); 2.53 (s, 6H); 1.00 (t, 3H).

PREPARATION IXN-(2-hydroxyethyl)-4-methoxy-2,6-dimethyl-N-(1-methylethyl)benzene-sulphonamide

In operating analogously to preparation I, starting with2-[(1-methylethyl)amino]ethanol, the product sought after is obtained asa colourless oil (yield=58%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.68 (t, 1H); 3.80 (s, 3H); 3.73(quin, 1H); 3.27 (dt, 2H); 3.20 (q, 2H); 3.12 (t, 2H); 2.53 (s, 6H);1.06 (d, 6H); 0.99 (t, 3H).

PREPARATION X[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl](1-methylethyl)amino]-ethoxy]aceticacid, 1,1-dimethylethyl ester

In operating analogously to preparation II, starting with the compoundobtained according to preparation IX, the product sought after isobtained as a colourless oil (yield=95%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 3.86 (s, 2H); 3.80 (s, 3H); 3.74(quin, 1H); 3.82 (m, 2H); 3.26 (m, 2H); 2.53 (s, 6H); 1.40 (s, 9H); 1.07(d, 6H).

PREPARATION XI[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl](1-methylethyl)amino]-ethoxy]aceticacid

In operating analogously to preparation III, starting with the compoundobtained according to preparation X, the product sought after isobtained as a white solid (yield=85%).

M.Pt.=96° C.

PREPARATION XIIN-cyclopropyl-N-(2-hydroxyethyl)-4-methoxy-2,6-dimethylbenzene-sulphonamide

In operating analogously to preparation I, starting with2-(cyclopropylamino)ethanol, the product sought after is obtained as awhite solid (yield=77%).

M.Pt.=58° C.

PREPARATION XIII[2-[cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulphonyl]amino]ethoxy]aceticacid, 1,1-dimethylethyl ester

In operating analogously to preparation II, starting with the compoundobtained according to preparation XII, the product sought after isobtained as a colourless oil (yield=84%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 3.98 (s, 2H); 3.80 (s, 3H); 3.69(t, 2H); 3.44 (t, 2H); 2.50 (s, 6H); 2.47 (m, 1H); 1.42 (s, 9H); 0.48(m, 2H); 0.16 (m, 2H).

PREPARATION XIV[2-[cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulphonyl]-amino]ethoxy]aceticacid

In operating analogously to preparation III, starting with the compoundobtained according to preparation XIII, the product sought after isobtained as a white solid (yield=85%).

M.Pt.=100° C.

PREPARATION XV 2,6-dichloro-4-methoxybenzenesulphonyl chloride and2,4-dichloro-6-methoxybenzenesulphonyl chloride

A solution is prepared of 15 g (84.7 mM) of 3,5-dichloroanisole in 8 mlof thionyl chloride that is cooled to −10° C., and 6 ml (90 mM) ofchlorosulphonic acid are then added dropwise. The reaction mixture isthen agitated for 3 hours at ambient temperature, and then poured over amixture of ice and ethyl acetate. The organic phase is separated, driedover magnesium sulphate and concentrated under reduced pressure. Theresidue from evaporation is used, without other purification, in thenext step.

PREPARATION XVIa2,6-dichloro-N-(2-hydroxyethyl)-4-methoxy-N-methyl-benzenesulphonamidePREPARATION XVIb2,4-dichloro-N-(2-hydroxyethyl)-6-methoxy-N-methyl-benzenesulphonamide

In operating analogously to preparation I, starting with the sulphonylchlorides obtained according to preparation XV, the products soughtafter are obtained as white solids, after separation of the compoundsand purification by silica gel chromatography, in eluting with the aidof a toluene/isopropanol mixture (95/5; v/v).

PREPARATION XVIa (yield=13%): M.Pt.=47° C. PREPARATION XVIb (yield=48%):M.Pt.=100° C. PREPARATION XVII[2-[[(2,6-dichloro-4-methoxyphenyl)sulphonyl]methylamino]-ethoxy]aceticacid, 1,1-dimethylethyl ester

In operating analogously to preparation II, starting with the compoundobtained according to preparation XVIa, the product sought after isobtained as a colourless oil (yield=52%).

¹H NMR (300 MHz, DMSO) δ: 7.24 (s, 2H); 3.94 (s, 2H); 3.87 (s, 3H); 3.60(t, 2H); 3.39 t, 2H); 2.90 (s, 3H); 1.41 (s, 9H).

PREPARATION XVIII[2-[[(2,6-dichloro-4-methoxyphenyl)sulphonyl]methylamino]-ethoxy]aceticacid

In operating analogously to preparation III, starting with the compoundobtained according to preparation XVII, the product sought after isobtained as a white solid (yield=94%).

M.Pt.=95° C.

PREPARATION XIX[2-[[(2,4-dichloro-6-methoxyphenyl)sulphonyl]methylamino]ethoxy]aceticacid, 1,1-dimethylethyl ester

In operating analogously to preparation II, starting with the compoundobtained according to preparation XVIb, the product sought after isobtained as an oil which is used, without other purification, in thenext step.

PREPARATION XX[2-[[(2,4-dichloro-6-methoxyphenyl)sulphonyl]methylamino]ethoxy]aceticacid

In operating analogously to preparation III, starting with the compoundobtained according to preparation XIX, the product sought after isobtained as a white solid (yield=76%).

M.Pt.=74° C.

PREPARATION XXI2,4-dichloro-N-(2-hydroxyethyl)-3,N-dimethyl-benzenesulphonamide

In operating analogously to preparation I, starting with2,4-dichloro-3-methylbenzenesulphonyl chloride, the product sought afteris obtained as a colourless oil.

PREPARATION XXII[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]aceticacid, 1,1-dimethylethyl ester

In operating analogously to preparation II, starting with the compoundobtained according to preparation XXI, the product sought after isobtained as a colourless oil (yield=87%).

¹H NMR (300 MHz, DMSO) δ: 7.83 (d, 1H); 7.63 (d, 1H); 3.93 (s, 2H); 3.59(t, 2H); 3.39 (t, 2H); 2.91 (s, 3H); 2.49 (s, 3H); 1.41 (s, 9H).

PREPARATION XXIII[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]aceticacid

In operating analogously to preparation III, starting with the compoundobtained according to preparation XXII, the product sought after isobtained as a colourless oil (yield=100%).

¹H NMR (300 MHz, DMSO) δ: 12.50 (m broad, 1H); 7.84 (d, 1H); 7.63 (d,1H); 4.02 (s, 2H); 3.61 (t, 2H); 3.40 (t, 2H); 2.91 (s, 3H); 2.51 (s,3H).

PREPARATION XXIVN-(2-hydroxyethyl)-N-methyl-2-(trifluoromethyl)benzenesulphonamide

In operating analogously to preparation I, starting with2-(trifluoromethyl)benzenesulphonyl chloride, the product sought afteris obtained as a yellow oil (yield=99%).

¹H NMR (250 MHz, DMSO) δ: 8.02 (m, 2H); 7.88 (m, 2H); 4.84 (t, 1H); 3.55(q, 2H); 3.30 (t, 2H); 2.93 (s, 3H).

PREPARATION XXV[2-[[[2-(trifluoromethyl)phenyl]sulphonyl]methylamino]-ethoxy]aceticacid, 1,1-dimethylethyl ester

In operating analogously to preparation II, starting with the compoundobtained according to preparation XXIV, the product sought after isobtained as a yellow oil (yield=67%).

¹H NMR (250 MHz, DMSO) δ: 8.02 (m, 2H); 7.98 (m, 2H); 3.97 (s, 2H); 3.63(t, 2H); 3.44 (t, 2H); 2.95 (s, 3H); 1.42 (s, 9H).

PREPARATION XXVI[2-[[[2-(trifluoromethyl)phenyl]sulphonyl]methylamino]-ethoxy]aceticacid

In operating analogously to preparation III, starting with the compoundobtained according to preparation XXV, the product sought after isobtained as a colourless oil (yield=78%).

¹H NMR (250 MHz, DMSO) δ: 8.02 (m, 2H); 7.86 (m, 2H); 4.01 (s, 2H); 3.65(t, 2H); 3.45 (t, 2H); 2.95 (s, 3H).

PREPARATION XXVII[2-[[[4-methoxy-2-(trifluoromethyl)phenyl]sulphonyl]-methylamino]ethoxy]aceticacid

A suspension is prepared of 8 g (60 mM) of 2-(2-methylaminoethoxy)aceticacid in 100 ml of chloroform and 20 ml of acetonitrile, and, at ambienttemperature, 17 ml (120 mM) of triethylamine are added, then, dropwise,7.63 ml (60 mM) of chlorotrimethylsilane. The mixture is agitated at 60°C. for 2 hours and then cooled to ambient temperature and 17 ml (120 mM)of triethylamine and then 16.48 g (60 mM) of4-methoxy-2-(trifluoromethyl)benzenesulphonyl chloride in solution in 60ml of chloroform, are added slowly. The reaction mixture is kept underagitation at 5° C. for 16 hours, and then concentrated under reducedpressure. The residue is taken up into 150 ml of dichloromethane and istreated with 40 ml of an N solution of hydrochloric acid. The organicphase is separated, washed with water, and then extracted with twice 120ml of N sodium hydroxide. The basic aqueous phase is separated, washedwith 100 ml of dichloromethane and then acidified with a 5N solution ofhydrochloric acid. The precipitate formed is extracted with twice 80 mlof dichloromethane; the organic phase obtained is washed with water andthen dried over magnesium sulphate and concentrated under reducedpressure. The residue obtained is crystallised in isopropyl ether,separated off and dried. 6.32 g of the compound sought after are thusobtained as a white solid (yield=28%).

M.Pt.=60° C.

PREPARATION XXVIII 4-(3-quinuclidinyl)piperazine-1-carboxylic acid,1,1-dimethylethyl ester

1 g (8 mM) of quinuclidinone, 1.63 g (8.75 mM) of 1-piperazinecarboxylicacid t-butyl ester (1-Boc-piperazine) and 2.71 ml (9.1 mM) of titaniumisopropoxide are mixed and this mixture is kept under agitation for 1hour. 5 ml of ethanol and then 460 mg (7.3 mM) of sodiumcyanoborohydride are then added, and this mixture is agitated for 24hours at ambient temperature. 25 ml of water are added and agitation iscarried out for 15 minutes. The precipitate formed is separated off byfiltration and the filtrate is concentrated under reduced pressure. Theresidue is purified by NH₂ silica gel chromatography in eluting with theaid of a toluene/isopropanol mixture (95/5; v/v). 1 g of the compoundsought after are thus obtained as a white solid (yield=42%).

M.Pt.=174° C.

PREPARATION XXIX (3RS)-3-(1-piperazinyl)-1-azabicyclo[2.2.2]octane or:(3(RS)-3-(1-piperazinyl)quinuclidine)

A solution is prepared of 990 mg (3.35 mM) of the compound obtainedaccording to preparation XXVIII in 10 ml of trifluoroacetic acid and themixture is agitated for 30 minutes at 10° C. 30 ml of toluene are thenadded and concentration is carried out under reduced pressure. Theresidue is taken up into 25 ml of methanol and the solution is agitatedwith 20 g of Amberlite IRA 400 resin (OH⁻) for 1 hour at ambienttemperature. The resin is separated off by filtration, rinsed with 15 mlof methanol and the combined filtrates are concentrated under reducedpressure. 530 mg of the product sought after are thus obtained as awhite paste (yield=80%).

¹H NMR (300 MHz, DMSO) δ: 2.79 (m, 1H); 2.67 (m, 7H); 2.50 (m, 2H); 2.22(m, 4H); 1.91 (m, 1H); 1.85 (m, 1H); 1.58 (m, 2H); 1.32 (m, 1H); 1.22(m, 1H).

EXAMPLE 2N-[2-[2-[4-[(3RS)-1-azabicyclo[2.2.2]oct-3-yl-1-piperazinyl]-2-oxo-ethoxy]ethyl]-N,2,4,6-tetramethylbenzenesulphonamide,bis trifluoro-acetate

250 mg (0.32 mM) of TFP (tetrafluorophenol) grafted polystyrene resinare placed in 4 ml of DMF for 15 minutes, and 4 mg (0.03 mM) of4-(dimethylamino)pyridine, 103 mg (0.32 mM) of acid obtained accordingto preparation V and 76 μl (0.48 mM) of diisopropylcarbodiimide, arethen added. The mixture is kept under agitation for 18 hours, and theresin is then separated off by filtration, rinsed twice with 3 ml of DMFand allowed to react with 44 mg (0.225 mM) of the amine obtainedaccording to preparation XXIX, in 3 ml of DMF. The mixture is agitatedfor 1 hour at ambient temperature and the resin is separated off byfiltration and rinsed with twice 3 ml of DMF. The filtrates are combinedand treated with 20 mg of Amberlite IRA 400 resin (OH—), and then with20 mg of isocyanate grafted resin, and then concentrated under reducedpressure. The residue is purified by semi-preparative chromatography(conditions analogous to those of Example 1). 16 mg of the compoundsought after are thus obtained as a white solid (yield=8%).

M.Pt.=78-80° C.

EXAMPLE 3N-[2-[2-[4-[(3RS)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide

500 mg (1.51 mM) of acid obtained according to preparation III, 319 mg(1.65 mM) of EDCI, 2.26 mg (1.65 mg) of HOAT and 233 μl of triethylamineare mixed in 10 ml of DMF and this reaction mixture is kept underagitation at ambient temperature for 30 minutes. 334 mg of the amineobtained according to preparation XXIX are then added and agitation iscarried out for 20 hours at ambient temperature. The reaction mixture ispoured onto iced water and extracted with DCM. The organic phase isdried over magnesium sulphate and concentrated under reduced pressure.The residue is purified by NH₂ grafted silica gel chromatography ineluting with a toluene/isopropanol mixture (95/5; v/v). 140 mg of theproduct sought after are thus obtained as a colourless oil (yield=18%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.05 (s, 2H); 3.80 (s, 3H); 3.53(t, 2H); 3.41 (m, 2H); 3.31 (m, 2H); 3.22 (t, 2H); 2.85 (m, 1H); 2.70(s, 3H); 2.57 (m, 5H); 2.53 (s, 6H); 2.27 (m, 4H); 1.90 (m, 2H); 1.60(m, 2H); 1.35 (m, 1H); 1.20 (m, 1H).

EXAMPLE 4N-[2-[2-[4-[(3RS)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

A solution is prepared of 137 mg (0.269 mM) of the compound obtainedaccording to Example 3 in 3 ml of methanol and 62.5 mg (0.538 mM) offumaric acid are added. The mixture is agitated for 30 minutes and thenconcentrated under reduced pressure. The residue is taken up into 5 mlof water and is freeze-dried. 200 mg of the salt sought after are thusobtained as a white powder (quantitative yield).

M.Pt.=86-90° C.

EXAMPLE 5N-[2-[2-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide

840 mg (2.53 mM) of acid obtained according to preparation III are mixedin 8 ml of anhydrous toluene and 0.1 ml of DMF. 0.245 ml (2.81 mM) ofoxalyl chloride are added slowly. The reaction mixture is agitated foran hour at ambient temperature and is then concentrated under reducedpressure. The residue is taken up into 10 ml of toluene and is addeddropwise to a solution of 0.5 g (2.56 mM) of3(S)-(1-piperazinyl)quinuclidine and 0.39 ml (2.81 mM) of triethylaminein 10 ml of toluene. The reaction mixture is agitated for an hour atambient temperature and 2 ml of ethanol and 10 g of silica gel forchromatography are then added. The solvents are removed under reducedpressure and the product which is adsorbed on the silica is purified bysilica gel chromatography in eluting with the aid of an ethylacetate/ethanol/aqueous ammonia mixture (6/3/1; v/v/v). The purefractions are concentrated under reduced pressure, taken up intosolution in ethyl acetate, dried over magnesium sulphate andconcentrated. The product sought after is thus obtained as a colourlessoil (yield=71%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.06 (t, 2H); 3.80 (s, 3H); 3.53(t, 2H); 3.41 (m, 2H); 3.31 (m, 2H); 3.22 (t, 2H); 2.85 (m, 1H); 2.69(s, 3H); 2.57 (m, 5H); 2.53 (s, 6H); 2.27 (m, 4H); 1.90 (m, 2H); 1.60(m, 2H); 1.35 (m, 1H); 1.20 (m, 1H).

EXAMPLE 6N-[2-[2-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

0.84 g (1.65 mM) of the compound obtained according to Example 5 aredissolved in 50 ml of methanol and 0.192 g (1.64 mM) of fumaric acid areadded. The mixture is agitated until complete dissolution and isconcentrated under reduced pressure. The residue is taken up intosolution in 40 ml of water, the solution is filtered and freeze-dried. 1g of the salt sought after are thus obtained as a white powder(yield=97%).

M.Pt.=86° C.

[α]²⁵ _(D)=−6.5° (C=0.31; CH₃OH)

EXAMPLE 7N-[2-[2-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

The racemic mixture obtained according to Example 3 is separated bychromatography on chiral phase (Chiralpack AD column) in eluting with ahexane/ethanol/isopropanol/trifluoroacetic acid mixture (60/25/15/0.05).Starting with 500 mg of the racemic mixture, 260 mg of enantiomer S and100 mg of enantiomer R are obtained. Each enantiomer is placed insolution in methanol and treated with 1 g of Amberlite IRA 400 resin(OH⁻). The treated solution is filtered and concentrated under reducedpressure and the basic compounds obtained are salified with fumaricacid, analogously to the operation described for Example 6. 143 mg ofenantiomer S and 68 mg of enantiomer R are thus obtained.

M.Pt.=84° C.

[α]²⁷ _(D)=7.2° (C=0.31; CH₃OH)

PREPARATION XXX4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazine-carboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation XXVIII, starting with8-methyl-8-azabicyclo[3.2.1]octan-3-one (tropinone), the ester soughtafter is obtained as a white solid (yield=53%)

¹H NMR (300 MHz, DMSO) δ: 3.25 (m, 4H); 3.15 (m, 2H); 2.51 (m, 2H); 2.35(m, 4H); 2.20 (s, 3H); 1.92 (m, 3H); 1.53 (m, 4H); 1.38 (s, 9H).

PREPARATION XXXI 8-methyl-3-(1-piperazinyl)-8-azabicyclo[3.2.1]octane

In operating analogously to preparation XXIX, starting with the compoundobtained according to preparation XXX, the product sought after isobtained as a yellow oil (yield=99%).

¹H NMR (300 MHz, DMSO) δ: 3.70 (m, 2H); 3.03 (m, 4H); 2.75 (m, 1H); 2.61(m, 4H); 2.53 (s, 3H); 2.10 (m, 2H); 1.75 (m, 6H).

PREPARATION XXXII4-(1-azabicyclo[2.2.2]oct-3-yl)hexahydro-1H-1,4-diazepine-1-carboxylicacid, 1,1-dimethylethyl ester

In operating analogously to preparation XXVIII, starting with1-homopiperazinecarboxylic acid t-butyl ester, the product sought afteris obtained as a colourless paste (yield=67%).

¹H NMR (300 MHz, DMSO) δ: 3.34 (m, 4H); 2.81-2.35 (m, 11H); 1.88 (m,1H); 1.65 (m, 4H); 1.39 (s, 9H); 1.34 (m, 1H); 1.18 (m, 1H).

PREPARATION XXXIII3-(hexahydro-1-1,4-diazepine-1-yl)-1-azabicyclo[2.2.2]octane

In operating analogously to preparation XXIX, starting with the compoundobtained according to preparation XXXII, the product sought after isobtained as a yellow oil (yield=98%).

¹H NMR (250 MHz, DMSO) δ: 3.41 (m, 1H); 3.11 (m, 8H); 2.96 (m, 1H); 2.78(m, 4H); 2.52 (m, 1H); 2.24 (m, 1H); 1.89 (m, 4H); 1.85 (m, 1H); 1.62(m, 1H).

In operating analogously to Example 1, starting with kown piperazinederivatives described in the literature or described above, thefollowing Examples are prepared:

EXAMPLE 81-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]-acetyl]-4-[3-(1-pyrrolidinyl)propyl]piperazine,bis-trifluoroacetate

Yield=90% (colourless paste). ¹H NMR (300 MHz, CD₃CN) δ: 6.74 (s, 2H);4.12 (s, 2H); 3.81 (s, 3H); 3.78 (m, 4H); 3.62 (t, 2H); 3.34 (t, 2H);3.27 (m, 12H); 2.73 (s, 3H); 2.57 (s, 6H); 2.22 (m, 2H); 2.03 (m, 4H).

EXAMPLE 91-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]-acetyl]-4-[2-(4-morpholinyl)ethyl]piperazine,bis-trifluoroacetate

Yield=51% (colourless paste)

¹H NMR (300 MHz, CD₃CN) δ: 6.75 (s, 2H); 4.11 (s, 2H); 3.92 (m, 4H);3.81 (s, 3H); 3.76 (m, 4H); 3.61 (t, 2H); 3.48 (m, 4H); 3.35 (t, 2H);3.27 (m, 8H); 2.72 (s, 3H); 2.57 (s, 6H).

EXAMPLE 101-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-4-[2-(1-piperidinyl)ethyl]piperazine,bis-trifluoroacetate

Yield=92% (colourless paste)

¹H NMR (300 MHz, CD₃CN) δ: 6.74 (s, 2H); 4.10 (s, 2H); 3.81 (s, 3H);3.81 (m, 4H); 3.61 (t, 2H); 3.40 (m, 2H); 3.34 (m, 4H); 3.24 (m, 4H);3.09 (m, 4H); 2.74 (s, 3H); 2.57 (s, 6H); 1.90 (m, 4H); 1.64 (m, 2H).

EXAMPLE 111-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-4-[3-(1-piperidinyl)propyl]piperazine,bis-trifluoroacetate

Yield=85% (colourless paste).

¹H NMR (300 MHz, CD₃CN) δ: 6.74 (s, 2H); 4.10 (s, 2H); 3.96 (s, 3H);3.80 (m, 2H); 3.60 (t, 2H); 3.50 (m, 4H); 3.30 (t, 2H); 3.15 (m, 2H);3.10 (m, 4H); 2.80 (m, 4H); 2.75 (s; 3H); 2.55 (s, 6H); 2.20 (m, 2H);1.93 (m, 5H); 1.37 (m, 1H).

EXAMPLE 121-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]-acetyl]-4-[3-(dimethylamino)propyl]piperazine,bis-trifluoroacetate

Yield=74% (colourless paste)

¹H NMR (300 MHz, CD3CN) δ: 6.74 (s, 2H); 4.11 (s, 2H); 3.81 (s, 3H);3.78 (m, 4H); 3.63 (t, 2H); 3.31 (t, 2H); 3.22 (m, 4H); 3.15 (m, 4H);2.81 (s, 6H); 2.74 (s, 3H); 2.57 (s, 6H); 2.23 (m, 2H).

In operating analogously to Examples 3 and 4, starting with derivativesof piperazine or of homopiperazine described above, the followingExamples are prepared:

EXAMPLE 134-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,bis trifluoroacetate

Yield=74% (colourless paste)

¹H NMR (300 MHz, CD₃CN) δ: 6.74 (s, 2H); 4.11 (s, 2H); 3.81 (s, 3H);3.80 (m, 4H); 3.77 (d, 2H); 3.64 (m, 2H); 3.55 (m, 1H); 3.34 (t, 2H);3.26 (m, 4H); 3.01 (m, 2H); 2.79 (s, 3H); 2.74 (s, 3H); 2.57 (s, 6H);2.29 (m, 4H).

EXAMPLE 144-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-1-piperazinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide,fumarate

Yield=62% (white solid)

M.Pt.=88-90° C.

EXAMPLE 151-(1-azabicyclo[2.2.2]oct-3-yl)hexahydro-4-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-1H-1,4-diazepine,fumarate

Yield=47% (white solid)

M.Pt.=90° C.

PREPARATION XXXIV4-[1-(1,1-dimethylethyl)-4-piperidinyl]-1-piperazinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation XXVIII, starting with1-(1,1-dimethylethyl)-4-piperidinone and the benzyl ester of1-piperazinecarboxylic acid, the product sought after is obtained as awhite solid (yield=56%).

M.Pt.=70-72° C.

PREPARATION XXXV 1-[1-(1,1-dimethylethyl)-4-piperidinyl]piperazine

A solution is prepared of 570 mg (1.59 mM) of the compound obtainedaccording to preparation XXXIV in 20 ml of methanol and 114 mg of 10%palladium on carbon are added. The mixture is agitated under anatmosphere of hydrogen for 2 hours at ambient temperature and atatmospheric pressure. The catalyst is removed by filtration and thefiltrate is concentrated under reduced pressure. The crude product ispurified by silica gel chromatography in eluting with the aid of adichloromethane/methanol/aqueous ammonia mixture (90/10/1; v/v/v). 270mg of the compound sought after are thus obtained as a white powder(yield=75%).

M.Pt.=106° C.

PREPARATION XXXVI4-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-piperazinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation XXVIII, starting with9-methyl-9-azabicyclo[3.3.1]nonan-3-one and the benzyl ester of1-piperazinecarboxylic acid, the product sought after is obtained as apale yellow solid (yield=18%).

M.Pt.=74° C.

PREPARATION XXXVII 1-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)piperazine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation XXXVI, the product sought after isobtained as a yellow oil (yield=100%).

¹H NMR (300 MHz, D2O) δ: 3.74 (m, 2H); 3.59 (m, 1H); 3.43 (m, 4H); 3.15(m, 4H); 3.01 and 2.97 (2s, 3H); 2.46 (dd, 1H); 2.30 (m, 2H); 2.10 (m,4H); 1.83 (m, 3H).

PREPARATION XXXVIII4-(11,2,2,6,6-pentamethyl-4-piperidinyl)-1-piperazinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation XXVIII, starting with1,2,2,6,6-pentamethyl-4-piperidinone and the benzyl ester of1-piperazinecarboxylic acid, the product sought after is obtained as acolourless oil (yield=52%).

¹H NMR (300 MHz, DMSO) δ: 7.36 (m, 5H); 5.07 (s, 2H); 3.37 (m, 4H); 2.85(m, 1H); 2.50 (m, 7H); 1.80 (m, 2H); 1.48 (m, 2H); 1.28 (s, 6H); 1.21(s, 6H).

PREPARATION XXXIX 1-(1,2,2,6,6-pentamethyl-4-piperidinyl)piperazine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation XXXVIII, the product sought after isobtained as a white solid (yield=35%).

M.Pt.=65° C.

PREPARATION XL4-[1-(1-methylethyl)-4-piperidinyl]-1-piperazinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation XXVIII, starting with1-(1-methylethyl)-4-piperidinone, the product sought after is obtainedas a yellow solid (yield=31%).

M.Pt.=53° C.

PREPARATION XLI 1-[1-(1-methylethyl)-4-piperidinyl]piperazine,trihydrochloride

A solution is prepared of 247 mg (0.79 mM) of the compound obtainedaccording to preparation XL in 1 ml of methanol, and 15 ml of a 2.3 Nsolution of hydrogen chloride in ethyl acetate are added. The mixture isagitated for 4 hours at ambient temperature. The reaction mixture isconcentrated under reduced pressure. 239 mg of the compound sought afterare thus obtained as a white powder. (yield=75%).

M.Pt.=262° C.

PREPARATION XLII 4-(1-cyclopropyl-4-piperidinyl)-1-piperazinecarboxylicacid, phenylmethyl ester

In operating analogously to preparation XXXIV, starting with1-cyclopropyl-4-piperidinone, the product sought after is obtained as awhite solid (yield=67%).

M.Pt.=88° C.

PREPARATION XLIII 1-(1-cyclopropyl-4-piperidinyl)piperazine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation XLII, the product sought after isobtained as a white solid (yield=92%).

M.Pt.=58° C.

PREPARATION XLIV4-(1-methyl-4-piperidinyl)hexahydro-1H-1,4-diazepine-1-carboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation XXXII, starting with1-methyl-4-piperidinone, the product sought after is obtained as ayellow oil (yield=78%).

¹H NMR (250 MHz, CDCl3) δ: 3.43 (m, 4H); 3.10 (dm, 2H); 2.70 (m, 4H);2.61 (m, 1H); 2.44 (s, 3H); 2.28 (m, 2H); 1.86 (m, 6H); 1.45 (s, 9H).

PREPARATION XLV 1-(1-methyl-4-piperidinyl)hexahydro-1H-1,4-diazepine,trihydrochloride

In operating analogously to preparation XLI, starting with the compoundobtained according to preparation XLIV, the product sought after isobtained as a beige solid (yield=99%).

M.Pt.=186° C.

PREPARATION XLVI4-(8-cyclopropyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester

In operating analogously to preparation XXVIII, starting with8-cyclopropyl-8-azabicyclo[3.2.1]octan-3-one, the ester sought after isobtained as a white paste (yield=45%).

¹H NMR (300 MHz, DMSO) δ: 3.24 (m, 6H); 2.50 (m, 5H); 2.34 (t, 4H); 1.87(m, 3H); 1.48 (dd, 6H); 1.38 (s, 9H); 0.36 (m, 2H); 0.25 (m, 2H).

PREPARATION XLVII

8-cyclopropyl-3-(1-piperazinyl)-8-azabicyclo[3.2.1]octane

In operating analogously to preparation XXIX, starting with the compoundobtained according to preparation XLVI, the product sought after isobtained as a white solid (yield=95%).

¹H NMR (250 MHz, CDCl3) δ: 3.37 (m, 2H); 2.94 (t, 2H); 2.58 (m, 4H);2.51 (m, 1H); 1.96 (m, 3H); 1.74 (t, 2H); 1.54 (m, 4H); 0.43 (d, 4H).

PREPARATION XLVIII4-[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]-1-piperazinecarboxylicacid, phenylmethyl ester

In operating analogously to preparation XXXIV, starting with the t-butylester of 4-oxo-1-piperidinecarboxylic acid, the product sought after isobtained as a yellow oil (yield=30%).

¹H NMR (250 MHz, DMSO) δ: 7.35 (m, 5H); 5.06 (s, 2H); 3.93 (d, 2H); 3.36(m, 4H); 2.68 (t, 2H); 2.44 (t, 4H); 2.37 (m, 1H); 1.66 (m, 2H); 1.38(s, 9H); 1.26 (m, 2H).

PREPARATION IL 4-(4-piperidinyl)-1-piperazinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation XXIX, starting with the compoundobtained according to preparation XLVIII, the product sought after isobtained as a yellow oil (yield=100%).

¹H NMR (250 MHz, DMSO) δ: 8.91 (m broad, h); 8.63 (m broad, 1H); 7.36(m, 5H); 5.11 (s, 2H); 3.80 (m, 2H); 3.45 (m, 4H); 3.22 (m, 5H); 2.92(q, 2H); 2.20 (d, 2H); 1.82 (dq, 2H).

PREPARATION L 4-(1-ethyl-4-piperidinyl)-1-piperazinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation XXXIV, starting withacetaldehyde and the compound obtained according to preparation IL, theproduct sought after is obtained as a colourless oil (yield=72%).

¹H NMR (250 MHz, DMSO) δ: 7.34 (m, 5H); 5.07 (s, 2H); 3.90 (m, 7H); 3.02(q, 2H); 2.84 (m, 2H); 2.45 (t, 4H); 1.91 (m, 2H); 1.63 (m, 2H); 1.19(t, 3H).

PREPARATION LI 1-(1-ethyl-4-piperidinyl)piperazine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation L, the product sought after isobtained as a yellow oil (yield=71%).

¹H NMR (250 MHz, DMSO) δ: 2.90 (m, 6H); 2.52 (m, 4H); 2.30 (q, 2H); 2.17(tt, 1H); 1.85 (dt, 2H); 1.69 (m, 2H); 1.38 (dq, 2H); 0.97 (t, 3H).

PREPARATION LII4-[8-[(1,1-dimethylethoxy)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl]-1-piperazinecarboxylicacid, phenylmethyl ester

In operating analogously to preparation XXVIII, starting with thet-butyl ester of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid, theester sought after is obtained as a white solid (yield=40%).

¹H NMR (250 MHz, CD₃CN) δ: 7.33 (m, 5H); 5.07 (s, 2H); 4.13 (m, 2H);3.37 (t, 4H); 2.80 (hep, 1H); 2.43 (t, 4H); 1.87 (m, 2H); 1.62 (m, 6H);1.42 (s, 9H).

PREPARATION LIII 4-(8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinecarboxylicacid, phenylmethyl ester, hydrochloride

In operating analogously to preparation XLI, starting with the compoundobtained according to preparation LII, the product sought after isobtained as a colourless oil (yield=96%).

¹H NMR (250 MHz, DMSO) δ: 11.78 (m broad, 1H); 9.45 (s, 2H); 7.38 (m,5H); 5.11 (s, 3H); 4.09 (m, 4H); 3.95 (m, 1H); 3.43 (m, 4H); 3.07 (m,2H); 2.22 (m, 4H); 1.92 (m, 4H).

PREPARATION LIV4-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation XXXIV, starting withacetaldehyde and the compound obtained according to preparation LIII,the product sought after is obtained as a colourless oil (yield=99%).

¹H NMR (250 MHz, CD3CN) δ: 7.33 (m, 5H); 5.07 (s, 2H); 3.39 (m, 6H);2.63 (m, 1H); 2.56 (q, 2H); 2.42 (t, 4H); 1.93 (m, 2H); 1.61 (m, 6H);1.06 (t, 3H).

PREPARATION LV 1-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)piperazine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation LIV, the product sought after isobtained as a colourless oil (yield=78%).

¹H NMR (300 MHz, CDCl3) δ: 3.57 (m, 2H); 2.94 (t, 2H); 2.71 (q, 2H);2.59 (m, 4H); 2.52 (m, 1H); 1.99 (m, 4H); 1.64 (m, 4H).

PREPARATION LVI4-[8-(1-methylethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1-piperazinecarboxylicacid, phenylmethyl ester

In operating analogously to preparation XXXIV, starting with acetone andthe compound obtained according to preparation LIII, the product soughtafter is obtained as a colourless oil (yield=77%).

¹H NMR (250 MHz, CDCl3) δ: 7.32 (m, 5H); 5.12 (s, 2H); 3.64 (m, 2H);3.49 (t, 4H); 2.92 (quin, 1H); 2.59 (hep, 1H); 2.47 (m, 4H); 1.99 (m,2H); 1.82 (dt, 2H); 1.63 (m, 2H); 1.48 (m, 2H); 1.14 (d, 6H).

PREPARATION LVII1-[8-(1-methylethyl)-8-azabicyclo[3.2.1]oct-3-yl]piperazine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation LVI, the product sought after isobtained as a colourless oil (yield=82%).

¹H NMR (250 MHz, CDCl3) δ: 3.79 (m, 2H); 3.05 (quin, 1H); 2.98 (m, 4H);2.71 (hep, 1H); 2.61 (m, 4H); 2.13 (m, 2H); 1.95 (m, 2H); 1.65 (m, 4H);1.29 (d, 6H).

PREPARATION LVIIIHexahydro-1-methyl-4-(1-oxo-2-propenyl)-1H-1,4-diazepine

A solution is prepared of 20 g (175 mM) of N-methylhomopiperazine in 100ml of dichloromethane, to which is added, dropwise, at 0° C., a solutionof 15.85 g (175 mM) of acryloyl chloride in 20 ml of dichloromethane.The reaction mixture is agitated for 1 hour at 0° C., and then for 2hours at ambient temperature, and then hydrolysed with a solution of 12g of sodium carbonate in 20 ml of water. The mixture is decanted, theorganic phase is washed once with water and then dried over magnesiumsulphate and concentrated under reduced pressure. 23 g of the compoundsought after are thus obtained, as an orangy oil, which is used, withoutother purification, in the next step.

PREPARATION LIX4-[3-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-3-oxopropyl]-1-piperazinecarboxylicacid, phenylmethyl ester

A solution is prepared of 7 g (41 mM) of the compound obtained accordingto preparation LVIII in 100 ml of toluene, to which 11 g (50 mM) of thebenzyl ester of 1-piperazinecarboxylic acid are added. The reactionmixture is agitated for 16 hours under reflux of the solvent, and thenconcentrated under reduced pressure. The residue is taken up into ethylacetate and the organic phase is washed once with water and then driedover magnesium sulphate and concentrated under reduced pressure. Thecrude product is purified by silica gel chromatography in eluting withthe aid of a toluene/isopropanol/aqueous ammonia mixture (80/20/1;v/v/v). 4.1 g of the compound sought after are thus obtained as a yellowoil (yield=26%).

¹H NMR (250 MHz, DMSO) δ: 7.36 (m, 5H); 5.06 (s, 2H); 3.47 (m, 4H); 3.37(m, 4H); 2.50 (m, 8H); 2.35 (m, 4H); 2.24 and 2.21 (2s, 3H); 1.75 (m,2H).

PREPARATION LX1-[3-(hexahydro-4-methyl-111,4-diazepin-1-yl)-3-oxopropyl]piperazine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation LIX, the product sought after isobtained as a colourless oil (yield=65%).

¹H NMR (250 MHz, DMSO) δ: 3.48 (m, 4H); 2.67 (t, 4H); 2.48 (m, 8H); 2.30(t, 4H); 2.25 and 2.22 (2s, 3H); 1.73 (m, 2H).

PREPARATION LXI1-[3-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)propyl]piperazine

A suspension is prepared of 120 mg (3.1 mM) of lithium aluminium hydridein 3 ml of tetrahydrofuran (THF) and a solution of 800 mg (3.1 mM) ofthe compound obtained according to preparation LX in 10 ml of THF isadded. The reaction mixture is heated under gentle reflux of the solventfor 4 hours, and then cooled to ambient temperature. 200 mg of Glauber'ssalt are added to the reaction mixture and then, after around 15minutes, 50 ml of ethyl acetate are added. The suspension obtained isfiltered and the filtrate is concentrated under reduced pressure. Thecrude product is purified by silica gel chromatography in eluting withthe aid of a dichloromethane/methanol/aqueous ammonia mixture (80/20/10;v/v/v). The product sought after is thus obtained as a colourless oil(yield=34%).

¹H NMR (250 MHz, DMSO) δ: 2.64 (t, 4H); 2.57 (m, 4H); 2.49 (m, 4H); 2.38(t, 2H); 2.23 (m, 6H); 2.21 (s, 3H); 1.66 (quin, 2H); 1.52 (quin, 2H).

PREPARATION LXII4-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-2-oxoethyl]-1-piperazinecarboxylicacid, phenylmethyl ester

A solution is prepared of 10 g (87.5 mM) of N-methylhomopiperazine in200 ml of dichloromethane, to which 36.6 ml of triethylamine are added.The mixture is cooled to −78° C. and 6.97 ml of chloroacetyl chlorideare added dropwise. The reaction mixture is agitated for 1.5 hours at−78° C., and a solution of 19.3 g (87.6 mM) of the benzyl ester of1-piperazinecarboxylic acid in 10 ml of dichloromethane is then added.The mixture is then left to come back to ambient temperature, andagitation is carried out for 15 hours. The medium is then hydrolysedwith a solution of sodium carbonate. The mixture is decanted, theorganic phase is washed once with water and then dried over magnesiumsulphate and concentrated under reduced pressure. The crude product ispurified by silica gel chromatography in eluting with the aid of adichloromethane/methanol/aqueous ammonia mixture (90/10/5; v/v/v). Theproduct sought after is thus obtained as a yellow oil (yield=43%).

¹H NMR (250 MHz, DMSO) δ: 7.36 (m, 5H); 5.07 (s, 2H); 3.55 (m, 2H); 3.44(m, 2H); 3.38 (m, 4H); 3.16 (d, 2H); 2.60 (m, 2H); 2.44 (m, 6H); 2.24and 2.22 (2s, 3H); 1.76 (m, 2H).

PREPARATION LXIII1-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-2-oxoethyl]piperazine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation LXII, the product sought after isobtained as a colourless oil (yield=60%).

¹H NMR (250 MHz, DMSO) δ: 3.56 (m, 2H); 3.44 (m, 2H); 3.10 (d, 2H); 2.74(dd, 4H); 2.61 (m, 1H2.44 (m, 4H); 2.39 (m, 3H); 2.25 and 2.22 (2s, 3H);1.78 (m, 2H).

PREPARATION LXIV1-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)ethyl]piperazine

In operating analogously to preparation LXI, starting with the compoundobtained according to preparation LXIII, the product sought after isobtained as a yellow oil (yield=21%).

¹H NMR (300 MHz, DMSO) δ: 2.63 (m, 8H); 2.49 (m, 5H); 2.28 (m, 7H); 2.21(s, 3H); 1.66 (quin, 2H).

PREPARATION LXV 1-(1-oxo-2-propenyl)azetidine

In operating analogously to preparation LVIII, starting with azetidine,the product sought after is obtained as a yellow oil which is allowed toreact in the following preparation without purification.

PREPARATION LXVI 4-[3-(1-azetidinyl)-3-oxopropyl]-1-piperazinecarboxylicacid, phenylmethyl ester

In operating analogously to preparation LIX, starting with the compoundobtained according to preparation LXV, the product sought after isobtained as a yellow oil (yield=14%).

¹H NMR (250 MHz, DMSO) δ: 7.34 (m, 5H); 5.06 (s, 2H); 4.09 (t, 2H); 3.80(t, 2H); 3.35 (m, 4H); 2.48 (t, 2H); 2.33 (t, 4H); 2.16 (m, 4H).

PREPARATION LXVII 1-[3-(1-azetidinyl)-3-oxopropyl]piperazine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation LXVI, the product sought after isobtained as a yellow solid (yield=100%).

M.Pt.=50° C.

PREPARATION LXVIII 1-[3-(1-azetidinyl)propyl]piperazine

In operating analogously to preparation LXI, starting with the compoundobtained according to preparation LXVII, the product sought after isobtained as a yellow oil (yield=30%).

¹H NMR (300 MHz, DMSO) δ: 3.19 (m broad, 1H); 3.02 (t, 4H); 2.66 (t,4H); 2.25 (m, 8H); 1.93 (quin, 2H); 1.36 (quin, 2H).

PREPARATION LXIX α-[(dimethylamino)methyl]-4-piperidinemethanol

20 g (83.6 mM) of 2-[(dimethylamino)methyl]-4-pyridinemethanoldihydrochloride are dissolved in 200 ml of methanol at 50° C. 2 g ofplatinum oxide are then added under an atmosphere of nitrogen, and themixture is agitated under an atmosphere of hydrogen, at 50° C., under apressure of 300 hPa (3 bars), for 7 hours. This catalyst is then removedby filtration and the filtrate is concentrated under reduced pressure.The solid residue is taken up with 10 ml of 10N sodium hydroxide and 150ml of chloroform. The organic phase is separated and washed with asolution of sodium chloride, dried over magnesium sulphate andconcentrated under reduced pressure. The product sought after is thusobtained as an oil which crystallises (yield=87%).

M.Pt.=98° C.

PREPARATION LXX 4-(1-pyrrolidinylmethyl)piperidine

In operating analogously to preparation LXIX, starting with4-(1-pyrrolidinylmethyl)pyridine, the product sought after is obtainedas a yellow oil.

PREPARATION LXXI4-[(4-(1-methylethyl)-1-piperazinyl]-1-piperidinecarboxylic acid,phenylmethyl ester

A mixture is prepared of 827 mg (3.54 mM) of the benzyl ester of4-oxo-1-piperidinecarboxylic acid, 500 mg (3.9 mM) ofN-isopropylpiperazine and 1.2 g (4.25 mM) of titanium isopropoxide in 10ml of methanol. 148 mg of sodium borohydride are added under agitationand at ambient temperature. The reaction mixture is kept under agitationfor 16 hours, and then diluted with 20 ml of water. The suspensionobtained is filtered and the precipitate is washed with 30 ml of ethylacetate which is then used to extract the filtrate. The organic phaseobtained is washed with water and then dried over magnesium sulphate andconcentrated under reduced pressure. The yellow oil obtained is purifiedby silica gel chromatography in eluting with the aid of adichloromethane/methanol mixture (9/1; v/v). 235 mg of the productsought after are thus obtained as a white solid (yield=19%).

M.Pt.=55° C.

PREPARATION LXXII 4-[4-(1-methylethyl)-1-piperazinyl]piperidine

In operating analogously to preparation XXXV, starting with the esterobtained following preparation LXXI, the product sought after isobtained as a white solid (yield=98%).

M.Pt.=65° C.

PREPARATION LXXIII4-[(4-methyl-1-piperazinyl)methyl]-1-piperidinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation LXXI, starting withN-methylpiperazine and the benzyl ester of4-formyl-1-piperidinecarboxylic acid, the product sought after isobtained as a colourless oil (yield=52%)

¹H NMR (250 MHz, DMSO) δ: 7.34 (m, 5H); 5.05 (s, 2H); 3.98 (m, 2H); 2.77(m, 2H); 2.29 (m, 8H); 2.19 (s, 3H); 2.08 (d, 2H); 1.67 (m, 3H); 0.95(m, 2H).

PREPARATION LXXIV 4-[(4-methyl-1-piperazinyl)methyl]piperidine

In operating analogously to preparation XXXV, starting with the esterobtained following preparation LXXIII, the product sought after isobtained as a colourless oil (yield=77%).

¹H NMR (250 MHz, DMSO) δ: 2.89 (m, 2H); 2.51 (m, 2H); 2.28 (m, 8H); 2.12(s, 3H); 2.05 (d, 2H); 1.55 (m, 3H); 1.02 (m, 2H).

PREPARATION LXXV 4-[(1-azetidinyl)methyl]-1-piperidinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation LXXIII, starting with azetidine,the product sought after is obtained as a colourless oil (yield=69%).

¹H NMR (300 MHz, DMSO) δ: 7.34 (m, 5H); 5.04 (s, 2H); 3.95 (m, 2H); 3.06(t, 4H); 2.75 (m, 2H); 2.18 (d, 2H); 1.94 (quin, 2H); 1.61 (m, 2H); 1.38(m, 1H); 0.94 (m, 2H).

PREPARATION LXXVI 4-[(1-azetidinyl)methyl]piperidine

In operating analogously to preparation XXXV, starting with the esterobtained following preparation LXXV, the product sought after isobtained as a colourless oil (yield=93%).

¹H NMR (250 MHz, DMSO) δ: 3.06 (t, 4H); 2.92 (m, 2H); 2.50 (m, 2H); 2.15(d, 2H); 1.91 (quin, 2H); 1.59 (m, 2H); 1.30 (m, 1H); 1.00 (m, 2H).

PREPARATION LXXVII 4-[(dimethylamino)methyl]-1-piperidinecarboxylicacid, phenylmethyl ester

In operating analogously to preparation LXXIII, starting withdimethylamine, the product sought after is obtained as a colourless oil(yield=78%).

¹H NMR (300 MHz, DMSO) δ: 7.35 (m, 5H); 5.05 (s, 2H); 3.97 (m, 2H); 2.79(m, 2H); 2.09 (s, 6H); 2.02 (d, 2H); 1.68 (d, 2H); 1.61 (m, 1H); 0.96(m, 2H).

PREPARATION LXXVIII 4-[(dimethylamino)methyl]piperidine

In operating analogously to preparation XXXV, starting with the esterobtained following preparation LXXVII, the product sought after isobtained as a colourless oil (yield=90%).

¹H NMR (300 MHz, DMSO) δ: 2.91 (m, 2H); 2.43 (m, 2H); 2.08 (s, 6H); 2.01(d, 2H); 1.59 (m, 2H); 1.49 (m, 1H); 0.96 (dq, 2H).

PREPARATION LXXIX4-[(4-ethyl-1-piperazinyl)methyl]-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation LXXIII, starting withN-ethylpiperazine and the t-butyl ester of4-formyl-1-piperidinecarboxylic acid, the product sought after isobtained as a colourless oil (yield=78%).

¹H NMR (300 MHz, DMSO) δ: 3.90 (m, 2H); 2.67 (m, 2H); 2.29 (m, 10H);2.09 (d, 2H); 1.63 (m, 3H); 1.38 (s, 9H); 0.96 (t, 3H); 0.85 (m, 2H).

PREPARATION LXXX 4-[(4-ethyl-1-piperazinyl)methyl]piperidine

In operating analogously to preparation XXIX, starting with the esterobtained following preparation LXXIX, the product sought after isobtained as a colourless oil (yield=76%).

¹H NMR (250 MHz, DMSO) δ: 2.95 (m, 2H); 2.51 (m, 2H); 2.42 (m, 10H);2.05 (d, 2H); 1.54 (m, 3H); 1.03 (m, 2H); 0.99 (t, 3H).

PREPARATION LXXXI4-[(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)methyl]-1-piperidine-carboxylicacid, 1,1-dimethylethyl ester

In operating analogously to preparation LXXIX, starting withN-methyl-homopiperazine, the product sought after is obtained as acolourless oil (yield=83%).

¹H NMR (300 MHz, DMSO) δ: no ¹H NMR

PREPARATION LXXXII4-[(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)methyl]piperidine

In operating analogously to preparation XXIX, starting with the esterobtained following preparation LXXXI, the product sought after isobtained as a colourless oil (yield=23%).

¹H NMR (250 MHz, DMSO) δ: 3.03 (m, 2H); 2.57 (m, 5H); 2.50 (m, 5H); 2.25(s, 2H); 2.22 (s, 3H); 1.68 (m, 4H); 1.63 (m, 1H); 1.08 (m, 2H).

PREPARATION LXXXIII4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation LXXI, starting withN-methyl-homopiperazine and the t-butyl ester of4-oxo-1-piperidinecarboxylic acid, the product sought after is obtainedas a yellow oil (yield=36%).

¹H NMR (250 MHz, CDCl3) δ: 4.15 (m, 2H); 2.82 (m, 4H); 2.70 (m, 7H);2.42 (s, 3H); 1.87 (m, 2H); 1.98 (m, 2H); 1.45 (s, 9H); 1.40 (m, 2H).

PREPARATION LXXXIV4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine, trihydrochloride

409 mg (1.37 mM) of the compound obtained according to preparationLXXXIII are dissolved in 1 ml of methanol and 27 ml of a 2.3 N solutionof hydrogen chloride in ethyl acetate are added. The mixture is agitatedat ambient temperature for 12 hours and then concentrated under reducedpressure. The product sought after is thus obtained as a beige foam(yield=99%).

¹H NMR (250 MHz, DMSO) δ: 3.88 (m, 4H); 3.62 (m, 1H); 3.43 (m, 6H); 2.94(m, 2H); 2.82 (s, 3H); 2.31 (m, 4H); 2.10 (m, 2H).

PREPARATION LXXXV 4-(4-cyclopropyl-1-piperazinyl)-1-piperidinecarboxylicacid, phenylmethyl ester

In operating analogously to preparation LXXI, starting withN-cyclopropylpiperazine, the product sought after is obtained as a whitesolid (yield=62%).

M.Pt.=64° C.

PREPARATION LXXXVI 4-(4-cyclopropyl-1-piperazinyl)piperidine

In operating analogously to preparation LXXII, starting with the esterobtained following preparation LXXXV, the product sought after isobtained as a white solid (yield=90%).

M.Pt.=107° C.

PREPARATION LXXXVII4-[4-(1,1-dimethylethyl)-1-piperazinyl]-1-piperidinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation LXXI, starting withN-t-butylpiperazine, the product sought after is obtained as a whitesolid (yield=50%).

M.Pt.=84° C.

PREPARATION LXXXVIII 4-[4-(1,1-dimethylethyl)-1-piperazinyl]piperidine

In operating analogously to preparation LXXII, starting with the esterobtained following preparation LXXXVII, the product sought after isobtained as a white solid (yield=75%).

M.Pt.=82° C.

PREPARATION LXXXIX 4-(4-piperidinyl)-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

A solution is prepared of 41 g (0.17 M) of 4,4′-bipiperidinedihydrochloride in 250 ml of ethanol and 250 ml of 2N sodium hydroxide.A solution of 18.5 g (0.085 M) of t-butyl dicarbonate in 100 ml ofethanol are added slowly, at 0° C. The reaction mixture is agitated for1 hour at 10° C. and the ethanol is then removed by an evaporator, underreduced pressure. The residual aqueous phase is saturated with sodiumchloride and extracted with ethyl acetate. The organic phase obtained isdried over magnesium sulphate and concentrated under reduced pressure.The crude product is purified by silica gel chromatography in elutingwith the aid of a dichloromehane/methanol/aqueous ammonia mixture(8/2/0.4; v/v/v). 16.5 g of the compound sought after are thus obtainedas a white solid (yield=72%).

M.Pt.=70-71° C.

PREPARATION XC 4-(1-ethyl-4-piperidinyl)-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation LXXI, starting with the esterobtained following preparation LXXXIX and acetaldehyde, the productsought after is obtained as a white solid (yield=87%).

M.Pt.=68-70° C.

PREPARATION XCI 4-(1-ethyl-4-piperidinyl)piperidine, dihydrochloride

In operating analogously to preparation LXXXIV, starting with the esterobtained following preparation XC, the product sought after is obtainedas a white solid (yield=100%).

M.Pt.=280° C.

PREPARATION XCII4-[1-(1-methylethyl)-4-piperidinyl]-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation XC, starting with the esterobtained following preparation LXXXIX and acetone, the product soughtafter is obtained as a colourless oil (yield=69%).

¹H NMR (250 MHz, CDCl3) δ: 4.10 (m, 2H); 3.52 (m, 1H); 3.47 (m, 2H);2.55 (m, 4H); 1.88 (m, 4H); 1.85 (m, 4H); 1.45 (s, 9H); 1.30 (d, 6H);1.12 (m, 2H).

PREPARATION XCIII 4-[1-(1-methylethyl)-4-piperidinyl]piperidine,dihydrochloride

In operating analogously to preparation LXXXIV, starting with the esterobtained following preparation XCII, the product sought after isobtained as a white solid (yield=89%).

M.Pt.=250° C.

PREPARATION XCIV 4-(1-cyclopropyl-4-piperidinyl)-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester

150 mg (0.56 mM) of the compound obtained according to preparationLXXXIX are dissolved in 5 ml of methanol and 320 μl of acetic acid and200 mg of 3 Å molecular sieves, and then 562 μl (2.79 mM) of1-ethoxy-1-(trimethylsilyloxy)cyclopropane and 141 mg (2.23 mM) ofsodium borohydride, are added. The reaction mixture is heated undergentle reflux for 20 hours, and then cooled and filtered. The filtrateis concentrated under reduced pressure and the residue from evaporationis taken up into 20 ml of ethyl acetate. This organic phase is washedwith a 2N solution of sodium hydroxide, and then with a saturatedsolution of sodium chloride, dried over magnesium sulphate andconcentrated under reduced pressure. The crude product is purified bysilica gel chromatography in eluting with the aid of adichloromehane/methanol mixture (95/5; v/v). 110 mg of the compoundsought after are thus obtained as a white powder (yield=64%).

¹H NMR (250 MHz, CDCl3) δ: 4.10 (m, 2H); 3.05 (m, 4H); 2.65 (t, 2H);2.09 (t, 2H); 1.67 (m, 4H); 1.55 (m, 1H); 1.45 (s, 9H); 1.22 (m, 6H);0.47 (m, 4H).

PREPARATION XCV 4-(1-cyclopropyl-4-piperidinyl)piperidine,dihydrochloride

In operating analogously to preparation LXXXIV, starting with the esterobtained following preparation XCIV, the product sought after isobtained as a white paste (yield=99%).

¹H NMR (250 MHz, DMSO) δ: 10.50 (m broad, 1H); 8.80 (m broad, 2H); 3.45(m, 2H); 3.16 (m, 2H); 2.81 (m, 2H); 2.73 (m, 3H); 1.90 (m, 4H); 1.60(m, 2H); 1.35 (m, 4H); 1.10 (m, 2H); 0.78 (m, 2H).

PREPARATION XCVI 4-[2-(4-piperidinyl)ethyl]-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation LXXXIX, starting with4,4′-ethylenedipiperidine hydrochloride, the product sought after isobtained as a white solid (yield=39%).

M.Pt.=92-94° C.

PREPARATION XCVII 4-[2-(1-methyl-4-piperidinyl)ethyl]piperidine

A solution is prepared of 307 mg (1.04 mM) of the ester obtainedfollowing preparation XCVI in 20 ml of anhydrous tetrahydrofuran (THF)and 157 mg (4.14 mM) of lithium aluminium hydride are added portionwise.The reaction mixture is agitated for 10 hours at 70° C. and then cooledand diluted with 30 ml of THF. 200 mg of Glauber's salt are added andthe mixture is left under agitation at ambient temperature overnight,and then filtered. The filtrate is concentrated under reduced pressureto give 235 mg of the product sought after as a white paste (yield=99%).

¹H NMR (300 MHz, DMSO) δ: 3.16 (s, 2H); 2.80 (m, 2H); 2.70 (m, 2H); 2.38(t, 2H); 2.10 (s, 3H); 1.76 (m, 2H); 1.58 (m, 3H); 1.42 (m, 1H); 1.11(m, 8H); 0.94 (m, 2H).

PREPARATION XCVIII 4-[2-(4-methyl-1-piperazinyl)ethyl]pyridine

In a tube, 2 ml (19 mM) of 4-vinylpyridine, 3.16 ml (28.5 mM) ofN-methylpiperazine, and 200 μl of acetic acid are mixed in 12 ml ofethanol. The tube is closed and heated for 10 minutes at 160° C. in amicrowave oven. After cooling, 20 ml of 0.5N sodium hydroxide are addedslowly and the mixture is extracted with dichloromethane. The separatedorganic phase is dried over magnesium sulphate and concentrated underreduced pressure. The product sought after is thus obtained as a yellowoil (yield=86%).

¹H NMR (250 MHz, DMSO) δ: 8.43 (dd, 2H); 7.25 (dd, 2H); 2.73 (t, 2H);2.52 (m, 2H); 2.48 (m, 4H); 2.30 (m, 4H); 2.13 (s, 3H).

In operating analogously to preparation XCVIII, the following pyridinederivatives are obtained:

PREPARATION IC 4-[2-(1-piperidinyl)ethyl]pyridine

yellow oil (yield=52%)

¹H NMR (250 MHz, DMSO) δ: 8.43 (dd, 2H); 7.24 (dd, 2H); 2.73 (t, 2H);2.49 (m, 2H); 2.37 (t, 2H); 1.43 (m, 6H).

PREPARATION C 4-[2-[(methyl)(1-methylethyl)amino]ethyl]pyridine

yellow oil (yield=10%).

¹H NMR (250 MHz, DMSO) δ: 8.49 (d, 2H); 7.16 (d, 2H); 2.76 (hep, 1H);2.65 (t, 2H); 2.56 (d, 2H); 2.15 (s, 3H); 0.90 (d, 6H).

PREPARATION CI 4-[2-(4-morpholinyl)ethyl]pyridine

yellow oil (yield=72%).

¹H NMR (250 MHz, DMSO) δ: 8.44 (dd, 2H); 7.26 (dd, 2H); 3.05 (dd, 4H);2.75 (t, 2H); 2.53 (m, 2H); 2.41 (dd, 2H).

PREPARATION CII 4-[2-(1-azetidinyl)ethyl]pyridine

yellow oil (yield=62%).

¹H NMR (300 MHz, DMSO) δ: 8.43 (d, 2H); 7.22 (d, 2H); 3.07 (t, 4H); 2.53(m, 4H); 1.91 (quin, 2H).

PREPARATION CIII (Methyl)[2-(4-pyridinyl)ethyl]carbamic acid,1,1-dimethylethyl ester

yellow oil (yield=83%).

¹H NMR (300 MHz, DMSO) δ: 8.45 (d, 2H); 7.21 (d, 2H); 3.42 (t, 2H); 2.76(t, 2H); 2.75 (s, 3H); 1.23 (s, 9H).

PREPARATION CIV 4-[2-[(methyl)(ethyl)amino]ethyl]pyridine

colourless oil (yield=51%).

¹H NMR (300 MHz, DMSO) δ: 8.50 (d, 2H); 7.25 (d, 2H); 2.73 (t, 2H); 2.55(t, 2H); 2.43 (q, 2H); 2.23 (s, 3H); 0.90 (t; 3H).

PREPARATION CV 4-[2-(diethylamino)ethyl]pyridine

yellow oil (yield=30%).

¹H NMR (250 MHz, DMSO) δ: 8.43 (dd, 2H); 7.24 (dd, 2H); 2.65 (m, 4H);2.40 (q, 4H); 0.93 (t, 6H).

PREPARATION CVI4-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)ethyl]pyridine

yellow oil (yield=52%)

¹H NMR (250 MHz, DMSO) δ: 8.43 (d, 2H); 7.25 (d, 2H); 2.71 (m, 8H); 2.50(m, 4H); 2.22 (s, 3H); 1.68 (m, 2H).

PREPARATION CVII 4-[2-(4-methyl-1-piperazinyl)ethyl]piperidine

In operating analogously to preparation LXIX, starting with the compoundobtained according to preparation XCVIII, the product sought after isobtained as a yellow solid (yield=80%).

M.Pt.=111-112° C.

PREPARATION CVIII 4-[2-(dimethylamino)ethyl]piperidine

In operating analogously to preparation CVII, starting with4-[2-(dimethylamino)ethyl]pyridine, the product sought after is obtainedas a colourless oil (yield=96%).

¹H NMR (300 MHz, DMSO) δ: 2.86 (2H); 2.39 (dt, 2H); 2.18 (dd, 2H); 2.08(s, 6H); 1.54 (dm, 2H); 1.27 (m, 3H); 0.96 (m, 2H).

PREPARATION CIX 4-[2-(1-pyrrolidinyl)ethyl]piperidine

In operating analogously to preparation CVII, starting with4-[2-(1-pyrrolidinyl)ethyl]pyridine, the product sought after isobtained as a colourless oil (yield=88%).

¹H NMR (300 MHz, DMSO) δ: 2.86 (dm, 2H); 2.38 (m, 8H); 1.64 (m, 4H);1.54 (dm, 2H); 1.32 (m, 3H); 0.96 (dq, 2H).

In operating analogously to preparation CVII, starting with thecompounds obtained according to preparations IC to CVI, the followingpiperidine derivatives are obtained

PREPARATION CX 4-[2-(1-piperidinyl)ethyl]piperidine

yellow oil (yield=92%). ¹H NMR (300 MHz, DMSO) δ: 3.10 (dm, 2H); 2.67(dt, 2H); 2.27 (m, 6H); 1.70 (m, 2H); 1.47 (m, 5H); 1.35 (m, 4H); 1.23(m, 2H).

PREPARATION CXI 4-[2-[(methyl)(1-methylethyl)amino]ethyl]piperidine

yellow oil (yield=96%).

¹H NMR (250 MHz, DMSO) δ: 3.10 (d, 2H); 2.77 (m, 1H); 2.60 (m, 2H); 2.35(t, 2H); 2.10 (s, 3H); 1.72 (m, 2H); 1.34 (m, 1H); 1.29 (t, 2H); 1.23(m, 2H); 0.91 (d, 6H).

PREPARATION CXII 4-[2-(4-morpholinyl)ethyl]piperidine

colourless oil (yield=98%).

¹H NMR (300 MHz, DMSO) δ: 3.54 (t, 4H); 2.86 (dt, 2H); 2.39 (dt, 2H);2.28 (m, 4H); 2.25 (t, 2H); 1.54 (dm, 2H); 1.31 (m, 3H); 0.97 (m, 2H).

PREPARATION CXIII 4-[2-(1-azetidinyl)ethyl]piperidine

colourless oil (yield=74%).

¹H NMR (250 MHz, DMSO) δ: 3.16 (t, 4H); 3.12 (m, 2H); 2.65 (m, 2H); 2.35(t, 2H); 1.94 (quin, 2H); 1.85 (m, 2H); 1.35 (m, 1H); 1.23 (t, 2H); 1.15(m, 2H).

PREPARATION CXIV (Methyl)[2-(4-piperidinyl)ethyl]carbamic acid,1,1-dimethylethyl ester

colourless oil (yield=64%).

¹H NMR (300 MHz, DMSO) δ: 3.16 (t, 2H); 2.89 (dm, 2H); 2.73 (s, 3H);2.40 (t, 2H); 1.38 (s, 9H); 1.35 (m, 2H); 0.96 (m, 2H).

PREPARATION CXV 4-[2-[(methyl)(ethyl)amino]ethyl]piperidine

colourless oil (yield=98%).

¹H NMR (300 MHz, DMSO) δ: 3.13 (m, 2H); 2.68 (m, 2H); 2.32 (m, 4H); 2.11(s, 3H); 1.85 (m, 2H); 1.51 (m, 1H); 1.34 (t, 2H); 1.24 (m, 2H); 0.96(t, 3H).

PREPARATION CXVI 4-[2-(diethylamino)ethyl]piperidine

yellow oil (yield=87%).

¹H NMR (250 MHz, DMSO) δ: 2.87 (dm, 2H); 2.40 (m, 8H); 1.54 (dm, 2H);1.26 (m, 3H); 0.98 (m, 2H); 0.91 (t, 6H).

PREPARATION CXVII4-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)ethyl]-piperidine

yellow oil (yield=79%).

¹H NMR (300 MHz, DMSO) δ: 2.89 (d, 2H); 3.05 (m, 2H); 2.58 (m, 4H); 2.49(m, 4H); 2.46 (m, 4H); 2.21 (s, 3H); 1.66 (m, 2H); 1.64 (m, 2H); 1.28(m, 3H); 0.99 (m, 2H).

PREPARATION CXVIII4-(2-hydroxy-1,1-dimethylethyl)-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation LXXXIX, starting withβ,β-dimethyl-4-piperidineethanol, the product sought after is obtainedas a colourless oil (yield=96%).

¹H NMR (300 MHz, DMSO) δ: 4.41 (t, 1H); 3.98 (d, 2H); 3.13 (d, 2H); 2.51(m, 2H); 1.50 (d, 2H); 1.38 (s, 9H); 1.33 (m, 1H); 1.04 (m, 2H); 0.93(s, 6H.

PREPARATION CXIX 4-(1,1-dimethyl-2-oxoethyl)-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester

A solution is prepared of 68 μl (0.77 mM) of oxalyl chloride in 6 ml ofanhydrous dichloromethane. 82.5 μl of dimethylsulphoxide are added at−70° C., and then, after 15 min, 100 mg (0.39 mM) of the alcoholobtained according to preparation CXVIII in solution in 4 ml ofdichloromethane are added. Then, after 5 min, 270 μl of triethylamineare added. The mixture is agitated 5 minutes at −70° C., and then leftto come back to ambient temperature. After addition of 25 ml of ethylacetate, this organic phase is washed with a 10% sodium bicarbonatesolution, dried over magnesium sulphate and concentrated under reducedpressure. The crude product is purified by silica gel chromatography ineluting with the aid of a dichloromethane/ethyl acetate mixture (85/15;v/v). 80 mg of the compound sought after are thus obtained as acolourless oil (yield=80%).

¹H NMR (250 MHz, DMSO) δ: 9.44 (s, 1H); 3.96 (d, 2H); 2.59 (m, 2H); 1.69(m, 1H); 1.50 (m, 2H); 1.38 (s, 9H); 1.07 (m, 2H); 0.93 (s, 6H).

PREPARATION CXX4-[2-(1-azetidinyl)-1,1-dimethylethyl]-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation LXXI, starting with the compoundobtained according to preparation CXIX and azetidine, the product soughtafter is obtained as a colourless oil (yield=65%).

¹H NMR (300 MHz, DMSO) δ: 3.96 (d, 2H); 3.13 (t, 4H); 2.51 (m, 2H); 2.16(s, 2H); 1.92 (quin, 2H); 1.55 (d, 2H); 1.39 (s, 9H); 1.35 (m, 1H); 1.05(m, 2H); 0.70 (s, 6H).

PREPARATION CXXI 4-[2-(1-azetidinyl)-1,1-dimethylethyl]piperidine,bis(trifluoroacetate)

520 mg (1.75 mM) of the compound obtained according to preparation CXXare mixed with 3 ml of trifluoroacetic acid and 380 μl of anisole in 3ml of dichloromethane. The mixture is agitated overnight at ambienttemperature and then concentrated under reduced pressure. The residue istaken up into 20 ml of toluene and again concentrated under reducedpressure. The crude product is triturated in 4 ml of ethyl ether to givea solid which is separated off by filtration and dried. 683 mg of thecompound sought after are thus obtained (yield=92%).

M.Pt.=138-140° C.

PREPARATION CXXXII4-[2-(4-morpholinyl)-1,1-dimethylethyl]-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation CXX, starting with morpholine,the product sought after is obtained as a colourless oil (yield=12%).

¹H NMR (300 MHz, DMSO) δ: 3.97 (d, 2H); 3.53 (t, 4H); 2.57 (m, 2H); 2.41(t, 4H); 2.10 (s, 2H); 1.60 (d, 2H); 1.38 (s, 9H); 1.29 (m, 1H); 1.05(m, 2H); 0.77 (s, 6H).

PREPARATION CXXIII 4-[2-(4-morpholinyl)-1,1-dimethylethyl]piperidine,bis(trifluoroacetate)

In operating analogously to preparation CXXI, starting with the compoundobtained according to preparation CXXII, the product sought after isobtained as a pale yellow solid (yield=69%).

M.Pt.=158-160° C.

PREPARATION CXXIV 4-[2-(1-piperidinyl)-1,1-dimethylethyl]pyridine

A suspension of 70 g (0.58 M) of 4-isopropylpyridine, 250 g (2 M) ofpiperidine hydrochloride and 85 g of paraformaldehyde in 600 ml of 95%ethanol is held under reflux for 48 hours. The reaction mixture is thenconcentrated under reduced pressure and the residue is taken up with 650ml of 3N sodium hydroxide and extracted with thrice 250 ml of ethylacetate. The combined organic phases are washed with a solution ofsodium chloride, dried and concentrated under reduced pressure. Thecrude product is distilled under a vacuum of 1 mm Hg and the fractioncollected between 80 and 125° C. is purified by silica gelchromatography in eluting with the aid of a toluene/isopropanol mixture(9/1; v/v). 21.4 g of the compound sought after are thus obtained as aclear yellow oil (yield=17%).

¹H NMR (300 MHz, CDCl3) δ: 8.49 (d, 2H); 7.32 (d, 2H); 2.53 (s, 2H);2.20 (t, 4H); 1.39 (m, 4H); 1.36 (m, 2H); 1.29 (s, 6H),

PREPARATION CXXV 4-[2-(1-piperidinyl)-1,1-dimethylethyl]piperidine

In operating analogously to preparation CVII, starting with the compoundobtained according to preparation CXXIV, the product sought after isobtained as a yellow oil (yield=33%).

¹H NMR (300 MHz, DMSO) δ: 2.94 (dm, 2H); 2.37 (m, 6H); 2.03 (s, 2H);1.45 (m, 6H); 1.32 (m, 2H); 1.18 (m, 1H); 1.05 (m, 2H); 0.74 (s, 6H).

In operating analogously to the preparations CXXIV and CXXV, the twofollowing compounds are obtained:

PREPARATION CXXVI 4-[2-(1-pyrrolidinyl)-11,1-dimethylethyl]piperidine

yellow oil (yield=72%).

¹H NMR (250 MHz, DMSO) δ: 2.97 (d, 2H); 2.55 (m, 4H); 2.48 (m, 2H); 2.26(s, 2H); 1.66 (m, 4H); 1.62 (d, 2H); 1.29 (m, 1H); 1.03 (m, 2H); 0.77(s, 6H).

PREPARATION CXXVII 4-[2-(diethylamino)-1,1-dimethylethyl]piperidine

colourless oil (yield=79%).

¹H NMR (300 MHz, DMSO) δ: no ¹H NMR

PREPARATION CXXVIIIN,1-dimethyl-N-[1-(phenylmethyl)-4-piperidinyl]-4-piperidinamine

In operating analogously to preparation LXXI, starting withN-methyl-4-piperidinone and 1-benzyl-4-(methylamino)piperidine, theproduct sought after is obtained as a yellow oil (yield=66%).

¹H NMR (300 MHz, DMSO) δ: 7.28 (m, 5H); 3.41 (s, 2H); 2.76 (m, 4H); 2.40(m, 2H); 2.12 (s, 3H); 2.10 (s, 3H); 1.90 (dt, 2H); 1.81 (dt, 2H); 1.57(dm, 4H); 1.44 (m, 4H).

PREPARATION CXXIX N,1-dimethyl-N-(4-piperidinyl)-4-piperidinamine

A solution is prepared of 980 mg (3.25 mM) of the compound obtainedaccording to preparation CXXVIII in 60 ml of methanol and 150 mg of 10%palladium on carbon are added. The mixture is agitated under anatmosphere of hydrogen, under a pressure of 50 PSI (3.5 bars or 3450hPa), at ambient temperature for 10 hours. The catalyst is removed byfiltration and the filtrate is concentrated under reduced pressure. Thecrude product obtained is purified by silica gel chromatography ineluting with the aid of a dichloromethane/methanol/aqueous ammoniamixture (97/3/0.3; v/v/v). The product sought after is obtained as ayellow oil (yield=29%).

¹H NMR (250 MHz, DMSO) δ: 2.94 (d, 2H); 2.76 (d, 2H); 2.43 (m, 4H); 2.12(s, 3H); 2.10 (s, 3H); 1.81 (m, 2H); 1.76 (m, 4H); 1.45 (m, 2H); 1.30(m, 2H).

PREPARATION CXXX 4-[2-oxo-2-(4-methyl-1-piperazinyl)ethyl]pyridine

A solution is prepared of 3 g (17.3 mM) of (4-pyridinyl)acetic acid in50 ml of tetrahydrofuran (THF) and, at ambient temperature, a solutionof 3.4 g (20.7 mM) of carbonyldiimidazole in solution in 50 ml of THF,is added dropwise. The reaction mixture is agitated for 8 hours, and asolution of 1.73 g (17.3 mM) of N-methylpiperazine in 20 ml of THF isthen added. The reaction mixture is heated under reflux of the solventfor 2 hours, and then concentrated under reduced pressure. The residuefrom evaporation is taken up with 80 ml of 3N sodium hydroxide andextracted with ethyl acetate. The organic phase is dried over magnesiumsulphate and concentrated under reduced pressure. The crude product ispurified by silica gel chromatography in eluting with the aid of adichloromethane/methanol mixture (99/1; v/v). The product sought afteris obtained as a colourless oil (yield=28%).

¹H NMR (250 MHz, DMSO) δ: 8.47 (dd, 2H); 7.23 (dd, 2H); 3.75 (s, 2H);3.46 (t, 2H); 2.23 (t, 4H); 2.15 (3H),

PREPARATION CXXXI 4-[2-oxo-2-(4-methyl-1-piperazinyl)ethyl]piperidine

In operating analogously to preparation CVII, starting with the compoundobtained according to preparation CXXX, the product sought after isobtained as a colourless oil (yield=59%).

¹H NMR (250 MHz, DMSO) δ: 3.42 (t, 4H); 3.28 (m, 2H); 2.87 (dt, 2H);2.41 (dt, 2H); 2.24 (m, 6H); 2.16 (s, 3H); 1.71 (m, 1H); 1.54 (dm, 2H);1.06 (dq, 2H).

In operating analogously to Examples 3 and 4, starting with the acidsand amines obtained above (or from amines known from the literature),the following compounds according to the invention are obtained:

EXAMPLE 16N-[2-[2-[4-[3-(1-azetidinyl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

Beige solid (yield=34%).

M.Pt.=82° C.

EXAMPLE 17N-[2-[2-[4-(1-methyl-3-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=36%).

M.Pt.=60-65° C.

EXAMPLE 18N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=51%).

M.Pt.=185° C.

EXAMPLE 19N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=42%).

M.Pt.=141° C.

EXAMPLE 20N-[2-[2-[4-[(1-methyl-2-imidazolyl)methyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=45%).

M.Pt.=60-65° C.

EXAMPLE 21N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=48%).

M.Pt.=206° C.

EXAMPLE 22N-[2-[2-[4-[3-(dimethylamino)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=26%).

M.Pt.=60° C.

EXAMPLE 23N-[2-[2-[4-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

White solid (yield=73%).

M.Pt.=96° C.

EXAMPLE 24N-[2-[2-[4-[3-(1-pyrrolidinyl)propyl]-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=63%).

M.Pt.=65° C.

EXAMPLE 25N-[2-[2-[4-[3-(1-pyrrolidinyl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate

Ecru solid (yield=61%).

M.Pt.=55° C.

EXAMPLE 26N-[2-[2-[4-(8-cyclopropyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

White solid (yield=81%).

M.Pt.=75° C.

EXAMPLE 27N-[2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=64%).

M.Pt.=185° C.

EXAMPLE 28N-[2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=51%).

M.Pt.=160° C.

EXAMPLE 29N-[2-[2-[4-(1-cyclopropyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=60%).

M.Pt.=112-114° C.

EXAMPLE 30N-[2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-(1-methylethyl)-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=60%).

M.Pt.=168° C.

EXAMPLE 31N-[2-[2-[4-(1-ethyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

Beige solid (yield=48%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 6.53 (s, 2H); 4.05 (s, 2H); 3.80(s, 3H); 3.53 (t, 2H); 3.39 (m, 2H); 3.29 (m, 2H); 3.22 (t, 2H); 3.12(m, 2H); 2.70 (s, 3H); 2.62 (q, 2H); 2.53 (s, 6H); 2.48 (m, 4H); 2.29(m, 3H); 1.77 (m, 2H); 1.52 (m, 2H); 1.07 (t, 2H).

EXAMPLE 32N-[2-[2-[4-[1-(1,1-dimethylethyl)-4-piperidinyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=41%).

M.Pt.=230° C.

EXAMPLE 33N-[2-[2-[4-[(1-methyl-4-piperidinyl)methyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

Yellow solid (yield=62%).

M.Pt.=50° C.

EXAMPLE 34N-[2-[2-[4-[3-(dimethylamino)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-methoxy-N-methyl-benzenesulphonamide,difumarate

White solid (yield=78%).

M.Pt.=60° C.

EXAMPLE 35N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-methoxy-N-methyl-benzenesulphonamide,difumarate

White solid (yield=69%).

M.Pt.=125° C.

EXAMPLE 36N-[2-[2-[4-[2-(1-methyl-4-piperidinyl)ethyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

Ecru solid (yield=62%).

M.Pt.=90° C.

EXAMPLE 37N-[2-[2-[4-(1-methyl-4-piperidinyl)hexahydro-1H-1,4-diazepin-1-yl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

White solid (yield=56%).

M.Pt.=53° C.

EXAMPLE 38N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-(1-methylethyl)-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=41%).

M.Pt.=170° C.

EXAMPLE 39N-[2-[2-[4-[1-(1-methylethyl)-4-piperidinyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

White solid (yield=81%).

M.Pt.=130° C.

EXAMPLE 40N-[2-[2-[4-[3-(1-piperidinyl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate

Ecru solid (yield=60%).

M.Pt.=65° C.

EXAMPLE 41N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4-dichloro-6-methoxy-N-methyl-benzenesulphonamide,difumarate

White solid (yield=46%).

M.Pt.=202° C.

EXAMPLE 42N-[2-[2-[4-(1-ethyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-methoxy-N-methyl-benzenesulphonamide,fumarate

White solid (yield=68%).

M.Pt.=96-98° C.

EXAMPLE 43N-[2-[2-[4-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-methyl-2,6-dichlorobenzenesulphonamide,fumarate

White solid (yield=36%).

M.Pt.=75-79° C.

In operating analogously to Example 2, starting with the acids andamines obtained above (or from amines known from the literature), and byusing the acid which is adapted for the salification of the purifiedbasic compound, the following compounds according to the invention areobtained:

EXAMPLE 44N-[2-[2-[4-(11,2,2,6,6-pentamethyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,bis(trifluoroacetate)

Colourless oil (yield=37%).

¹H NMR (300 MHz, CD3CN) δ: 8.70 (m broad, 1H); 6.75 (s, 2H); 4.10 (s,2H); 3.80 (s, 3H); 3.76 (m, 4H); 3.70 (t, 1H); 3.61 (t, 2H); 3.28 (m,4H); 2.27 (s, 6H); 2.57 (s, 6H); 2.28 (dm, 4H); 1.47 (s, 6H); 1.38 (s,6H).

EXAMPLE 45N-[2-[2-[4-[3-(4-methyl-1-piperazinyl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=30%).

M.Pt.=204° C.

EXAMPLE 46N-[2-[2-[4-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=27%).

M.Pt.=132° C.

EXAMPLE 47N-[2-[2-[4-[3-(4-methyl-hexahydro-1H-1,4-diazepin-1-yl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=45%).

M.Pt.=169° C.

EXAMPLE 48N-[2-[2-[4-[8-(1-methylethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=35%).

M.Pt.=132° C.

EXAMPLE 49N-[2-[2-[4-[3-(4-methyl-hexahydro-1H-1,4-diazepin-1-yl)-3-oxo-propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,bis(trifluoroacetate)

Colourless oil (yield=35%).

¹H NMR (300 MHz, CD3CN) δ: 6.76 (s, 2H); 4.15 (s, 2H); 3.84 (s, 3H);3.82 (m, 6H); 3.65 (t, 2H); 3.62 (m, 2H); 3.44 (t, 2H); 3.36 (m, 10H);2.90 (t, 2H); 2.87 (s, 3H); 2.77 (s, 3H); 2.61 (s, 6H); 2.18 (m, 2H).

EXAMPLE 50N-[2-[2-[4-[2-(4-methyl-hexahydro-1H-1,4-diazepin-1-yl)ethyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,trifumarate

White solid (yield=8%).

M.Pt.=176° C.

In operating analogously to Examples 5 and 4, starting with the acidsobtained above, the two following compounds according to the inventionare obtained:

EXAMPIE 51N-[2-[2-[4-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=37%).

M.Pt.=72° C.

[α_(D) ²⁵]=−11.4° (c=0.5; CH₃OH)

EXAMPLE 52N-[2-[2-[4-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate

White solid (yield=32%).

M.Pt.=70° C.

[α_(D) ²⁵]=−11° (c=0.5; CH₃OH)

In operating analogously to Example 1, starting with the acid obtainedaccording to preparation III and 1-[2-(diethylamino)ethyl]piperazine,the following compound according to the invention is obtained:

EXAMPLE 53N-[2-[2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

White pasty solid (yield=77%).

¹H NMR (300 MHz, CD3CN) δ: 6.74 (s, 2H); 6.60 (s, 2H); 4.02 (s, 2H);3.80 (s, 3H); 3.54 (t, 2H); 3.46 (m, 2H); 3.32 (m, 2H); 3.26 (t, 2H);2.96 (m, 6H); 2.74 (s, 3H); 2.62 (t, 2H); 2.57 (s, 6H); 2.41 (m, 4H);1.16 (t, 6H).

PREPARATION CXXXII [2-[methyl(phenylmethyl)amino]ethoxy]acetic acid,1,1-dimethylethyl ester

In operating analogously to preparation II, starting with2-[methyl(phenylmethyl)amino]ethanol, the product sought after isobtained as a colourless oil (yield=35%).

¹H NMR (250 MHz, DMSO) δ: 7.26 (m, 5H); 3.96 (s, 2H); 3.57 (t, 2H); 3.49(s, 2H); 2.49 (m, 2H); 2.14 (s, 3H); 1.40 (s, 9H).

PREPARATION CXXXIII [2-[methyl(phenylmethyl)amino]ethoxy]acetic acid,lithium salt

A solution of 1 g (3.58 mM) of the compound obtained according topreparation CXXXII in 10 ml of tetrahydrofuran is heated under thereflux of the solvent in the presence of 165 mg of lithia and 3 ml ofwater, for 8 hours. The reaction mixture is then concentrated underreduced pressure to give the product sought after as a colourless foam(yield=99%).

¹H NMR (250 MHz, DMSO) δ: 7.26 (m, 5H); 3.59 (s, 2H); 3.53 (t, 2H); 3.48(s, 2H); 2.50 (t, 2H); 2.12 (s, 3H).

PREPARATION CXXXIVN-methyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxoethoxy]ethyl]-benzenemethanamine

In operating analogously to Example 5, starting with the salt obtainedaccording to preparation CXXXIII and1-(1-methyl-4-piperidinyl)piperazine, the product sought after isobtained as a yellow oil (yield=24%).

¹H NMR (250 MHz, DMSO) δ: 7.26 (m, 5H); 4.09 (s, 2H); 3.54 (t, 2H); 3.49(s, 2H); 3.37 (m, 4H); 2.78 (m, 2H); 2.53 (t, 2H); 2.43 (m, 4H); 2.41(s, 3H); 2.11 (s, 3H); 2.07 (m, 1H); 1.80 (dt, 2H); 1.65 (dm, 2H); 1.39(dq, 2H).

PREPARATION CXXXVN-methyl-2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxoethoxy]ethanamine

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation CXXXIV, the product sought after isobtained as a yellow oil (yield=80%).

¹H NMR (300 MHz, DMSO) δ: 4.16 (s, 2H); 3.55 (t, 2H); 3.49 (m, 1H); 3.39(m, 2H); 3.33 (m, 2H); 2.77 (t, 4H); 2.43 (m, 2H); 2.38 (s, 3H); 2.16(m, 2H); 2.12 (s, 3H); 1.82 (dt, 2H); 1.67 (dm, 2H); 1.38 (dq, 2H).

PREPARATION CXXXVI 2,6-dichloro-4-fluorobenzenesulphonyl chloride

A solution of 4.75 g (25 mM) of 2,6-dichloro-4-fluoroaniline in 50 ml ofdichloromethane are added, at −15° C., to 4.75 ml of boron trifluorideetherate. 5 ml of tetrahydrofuran are added to dissolve the precipitateformed, then, slowly, 3.6 ml of t-butyl nitrite in solution in 25 ml ofdichloromethane are added. The reaction mixture is agitated 10 minutesat −15° C. and then 20 minutes at +5° C. 200 ml of pentane are added,and agitation is maintained at 0° C. for 30 min and the precipitate isfiltered off. After drying, 7.2 g of the diazonium salt are obtained.This salt is dissolved in 30 ml of acetonitrile and is added, at 10° C.,to a mixture of a solution of sulphur dioxide in 90 ml of acetic acid towhich 1.4 g of anhydrous copper (II) chloride and 23 ml of concentratedhydrochloric acid have been added. The reaction mixture is agitated 30min at ambient temperature and then concentrated under reduced pressure.The residue from evaporation is taken up into 60 ml of dichloromethaneand the insoluble salts are removed by filtration. The filtrate isconcentrated under reduced pressure to give 4.71 g of the product soughtafter as orange crystals (yield=71%).

M.Pt.=57° C.

EXAMPLE 54N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-fluoro-N-methyl-benzenesulphonamide

In operating analogously to preparation I, starting with the compoundsobtained according to preparations CXXXV and CXXXXVI, the product soughtafter is obtained as a pale yellow oil (yield=73%).

¹H NMR (250 MHz, DMSO) δ: 7.73 (d, 2H); 4.08 (s, 2H); 3.58 (t, 2H); 3.45(t, 2H); 3.40 (m, 2H); 3.30 (m, 2H); 2.93 (s, 3H); 2.78 (m, 2H); 2.41(m, 4H); 2.13 (m, 1H); 2.11 (s, 3H); 1.81 (t, 2H); 1.75 (m, 2H); 1.40(m, 2H).

EXAMPLE 55N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-fluoro-N-methyl-benzenesulphonamide,difumarate

In operating analogously to Example 4, starting with the compoundobtained according to Example 54, the product sought after is obtainedas a white solid (yield=76%).

M.Pt.=152-155° C.

In operating analogously to Examples 54 and 55, starting withbenzenesulphonyl chlorides having various substituents, the followingcompounds according to the invention are obtained:

EXAMPLE 56N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-bromo-2,6-dichloro-N-methyl-benzenesulphonamide

Colourless oil (yield=37%).

¹H NMR (300 MHz, DMSO) δ: 7.97 (s, 2H); 4.07 (s, 2H); 3.58 (t, 2H); 3.45(t, 2H); 3.43 (m, 2H); 2.99 (s, 3H); 2.74 (m, 2H); 2.42 (m, 4H); 2.14(m, 1H); 2.13 (s, 3H); 1.81 (t, 2H); 1.76 (m, 2H); 1.44 (m, 2H).

EXAMPLE 57N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-bromo-2,6-dichloro-N-methyl-benzenesulphonamide,difumarate

White solid (yield=87%).

M.Pt.=194° C.

EXAMPLE 58N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4,6-trichloro-N-methyl-benzenesulphonamide

Colourless oil (yield=64%).

¹H NMR (300 MHz, DMSO) δ: 7.88 (s, 2H); 4.08 (s, 2H); 3.58 (t, 2H); 3.44(t, 2H); 3.38 (m, 4H); 2.94 (s, 3H); 2.78 (m, 2H); 2.42 (m, 4H); 2.17(m, 1H); 2.11 (s, 3H); 1.81 (t, 2H); 1.76 (m, 2H); 1.44 (m, 2H).

EXAMPLE 59N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4,6-trichloro-N-methyl-benzenesulphonamide,difumarate

White solid (yield=82%).

M.Pt.=194° C.

EXAMPLE 60N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4-dichloro-6-methyl-N-methyl-benzenesulphonamide

Colourless oil (yield=61%).

¹H NMR (300 MHz, DMSO) δ: 7.70 (d, 1H); 7.56 (d, 1H); 4.07 (s, 2H); 3.57(t, 2H); 3.37 (m, 2H); 3.30 (s, 4H); 2.85 (s, 3H); 2.74 (m, 2H); 2.62(s, 3H); 2.42 (m, 4H); 2.13 (m, 1H); 2.11 (s, 3H); 1.81 (t, 2H); 1.77(m, 2H); 1.43 (m, 2H).

EXAMPLE 61N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4-dichloro-6-methyl-N-methyl-benzenesulphonamide,difumarate

White solid (yield=87%).

M.Pt.=190° C.

EXAMPLE 62N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-2,3,6-trimethyl-N-methyl-benzenesulphonamide

Colourless oil (yield=34%).

¹H NMR (250 MHz, DMSO) δ: 6.83 (s, 1H); 4.03 (s, 2H); 3.84 (s, 3H); 3.52(t, 2H); 3.35 (m, 2H); 3.35 (m, 2H); 3.18 (t, 2H); 2.73 (m, 2H); 2.69(s, 3H); 2.57 (s, 3H); 2.42 (s, 3H); 2.41 (t, 4H); 2.12 (s, 3H); 2.10(m, 1H); 2.08 (s, 3H); 1.81 (m, 2H); 1.66 (m, 2H); 1.38 (m, 2H).

EXAMPLE 634-methoxy-N,2,3,6-tetramethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=71%).

M.Pt.=180° C.

PREPARATION CXXXVII4-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester

In operating analogously to Example 5, starting with N-Boc-piperazine,the product sought after is obtained which is used in the next stepwithout particular purification.

PREPARATION CXXXVIII4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-(1-piperazinyl)ethoxy]ethyl]benzenesulphonamide

In operating analogously to preparation XXIX, starting with the compoundobtained following preparation CXXXVII, the product sought after isobtained as a yellow oil (yield=98%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.04 (s, 2H); 3.80 (s, 3H); 3.53(t, 2H); 3.30 (m, 2H); 3.23 (t, 4H); 2.70 (s, 3H); 2.60 (t, 4H); 2.53(s, 6H).

PREPARATION CXXXIX 4-(3-oxopropyl)-1-piperidinecarboxylic acid,phenylmethyl ester

0.81 ml of dimethylsulphoxide in solution in 10 ml of dichloromethane(DCM) is cooled to −50° C. and 0.42 ml (4.8 mM) of oxalyl chloride insolution in 1.5 ml of DCM are added. The mixture is agitated for 10minutes at −60° C. are then, at this temperature, 1.21 g (4.4 mM) of thebenzyl ester of 4-(3-hydroxypropyl)piperidinecarboxylic acid in solutionin 6 ml of DCM are added dropwise. The reaction mixture is agitated for30 minutes at −50° C. and 3 ml of triethylamine are then added dropwiseand the temperature is allowed to rise up to ambient temperature in 2hours. The mixture is hydrolysed on 25 ml of N hydrochloric acid andextracted with DCM. The organic phase is washed with water, dried overmagnesium sulphate and concentrated under reduced pressure. The crudeproduct is purified by silica gel chromatography in eluting with the aidof a cyclohexane/ethyl acetate mixture (75/25; v/v). The product soughtafter is thus obtained as a yellow oil (yield=83%).

¹H NMR (300 MHz, DMSO) δ: 9.66 (s, 1H); 7.35 (m, 5H); 5.05 (s, 2H); 3.98(m, 2H); 2.75 (m, 2H); 2.44 (m, 2H); 1.64 (q, 2H); 1.63 (m, 2H); 1.37(m, 1H); 1.02 (m, 2H).

PREPARATION CXL4-[3-[4-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-1-piperazinyl]propyl]-1-piperidinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation XXVIII, starting with thecompounds obtained following preparations CXXXVIII and CXXXIX, theproduct sought after is obtained as a colourless oil (yield=51%).

¹H NMR (300 MHz, DMSO) δ: 7.40 (m, 5H); 6.81 (s, 2H); 5.05 (s, 2H); 4.33(s, 2H); 3.96 (m, 2H); 3.79 (s, 3H); 3.55 (t, 2H); 3.37 (m, 2H); 3.30(m, 2H); 3.19 (t, 2H); 2.71 (m, 2H); 2.69 (s, 3H); 2.52 (s, 6H); 2.25(m, 6H); 1.65 (m, 2H); 1.42 (m, 3H); 1.20 (m, 2H); 1.00 (m, 2H).

EXAMPLE 644-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-[3-(4-piperidinyl)propyl]-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide

In operating analogously to preparation XXXV, starting with the compoundobtained following preparation CXL, the product sought after is obtainedas a colourless oil (yield=62%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.05 (s, 2H); 3.80 (s, 3H); 3.53(t, 2H); 3.30 (m, 4H); 3.19 (t, 2H); 2.88 (m, 2H); 2.69 (s, 3H); 2.50(s, 6H); 2.44 (m, 2H); 2.27 (m, 6H); 1.57 (m, 2H); 1.41 (m, 3H); 1.17(m, 2H); 0.97 (m, 2H).

EXAMPLE 654-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide

In operating analogously to preparation XXVIII, starting with thecompound obtained following Example 64, the product sought after isobtained as a colourless oil (yield=90%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.05 (s, 2H); 3.80 (s, 3H); 3.53(t, 2H); 3.38 (m, 2H); 3.24 (t, 2H); 3.18 (m, 2H); 2.72 (m, 2H); 2.69(s, 3H); 2.50 (s, 6H); 2.28 (m, 6H); 2.11 (s, 2H); 1.78 (m, 2H); 1.60(m, 2H); 1.45 (m, 2H); 1.15 (m, 5H).

EXAMPLE 664-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide,difumarate

In operating analogously to Example 4, starting with the compoundobtained following Example 65, the product sought after is obtained as awhite solid (yield=98%).

M.Pt.=50° C.

PREPARATION CXLI4-[4-(phenylmethyl)-1-piperazinyl]-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

In operating analogously to preparation XXVIII, starting withN-benzylpiperazine and N-Boc-4-piperidinone, the product sought after isobtained as a colourless oil (yield=60%).

¹H NMR (300 MHz, CDCl3) δ: 7.27 (m, 5H); 4.15 (m, 2H); 3.52 (s, 2H);2.61 (m, 11H); 1.81 (m, 2H); 1.44 (s, 9H); 1.41 (m, 2H).

PREPARATION CXLII 4-(1-piperazinyl)-1-piperidinecarboxylic acid,1,1-dimethylethyl ester

A solution is prepared of 15.5 g (43.1 mM) of the compound obtainedaccording to preparation CXLI in 46 ml of ethanol and 3.1 g of palladiumhydroxide are added, and then, after rendering the reactor inert, 17.7 g(215 mM) of cyclohexene are added. The reaction mixture is agitated at50° C. for 6 hours and then cooled and filtered. The filtrate isconcentrated under reduced pressure and 10.02 g of the product soughtafter are obtained as a colourless oil (yield=86%).

¹H NMR (300 MHz, CDCL3) δ: 4.12 (m, 2H); 2.92 (m, 4H); 2.69 (m, 2H);2.55 (t, 4H); 2.36 (m, 1H); 1.79 (m, 2H); 1.45 (s, 9H); 1.38 (m, 2H).

PREPARATION CXLIII4-[4-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]-methylaminoethoxy]acetyl]-1-piperazinyl]-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester

In operating analogously to Example 3, starting with the compoundsobtained following preparations III and CXLII, the product sought afteris obtained as a colourless oil (yield=32%).

¹H NMR (300 MHz, CD3CN) δ: 6.74 (s, 2H); 4.07 (m, 2H); 4.00 (s, 2H);3.80 (s, 3H); 3.54 (t, 2H); 3.43 (m, 2H); 3.26 (m, 4H); 2.74 (s, 3H);2.69 (m, 2H); 2.57 (s, 6H); 2.44 (m, 4H); 2.34 (m, 1H); 1.71 (m, 2H);1.41 (s, 9H); 1.29 (m, 2H).

EXAMPLE 674-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(4-piperidinyl)-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide,bis(trifluoroacetate)

A mixture is prepared of 140 mg (0.24 mM) of the compound obtainedaccording to preparation CXLIII in 1 ml of dichloromethane and 0.7 ml oftrifluoroacetic acid. The reaction mixture is agitated at ambienttemperature for 2 hours and then concentrated under reduced pressure.The residue from evaporation is taken up into 3 ml of water and isfreeze-dried. 160 mg of the product sought after are thus obtained as awhite solid (yield=95%).

M.Pt.=62° C.

PREPARATION CXLIV 4-(6-nitro-3-pyridinyl)-1-piperazinecarboxylic acid,1,1-dimethylethyl ester

A solution is prepared of 1 g (4.9 mM) of 2-nitro-5-bromopyridine and917 mg (4.9 mM) of N-Boc-piperazine in 10 ml of dimethylformamide and1.02 g (7.4 mM) of potassium carbonate are added. The reaction mixtureis agitated at 120° C. for 36 hours and then cooled. 50 ml of water arethen added and extraction is carried out with ethyl acetate. The organicphase obtained is washed with water, dried and concentrated underreduced pressure. The crude product is purified by silica gelchromatography in eluting with the aid of a toluene/isopropanol mixture(98/2; v/v). The product sought after is thus obtained as a yellow solid(yield=33%).

¹H NMR (250 MHz, DMSO) δ: 8.24 (d, 1H); 8.17 (d, 1H); 7.46 (dd, 1H);3.50 (m, 8H); 1.42 (s, 9H).

PREPARATION CXLV 1-(6-nitro-3-pyridinyl)piperazine,bis(trifluoroacetate)

In operating analogously to Example 67, starting with the compoundobtained following preparation CXLIV, the product sought after isobtained as a yellow solid (yield=97%).

M.Pt.=188-190° C.

PREPARATION CXLVI4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(6-nitro-3-pyridinyl)-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide

In operating analogously to Example 3, starting with the compoundsobtained following preparations III and CXLV, the product sought afteris obtained as a yellow solid (yield=82%).

M.Pt.=118-120° C.

EXAMPLE 684-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(6-amino-3-pyridinyl)-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide

A suspension is prepared of 580 mg (1.11 mM) of the compound obtainedfollowing preparation CXLVI in 20 ml of methanol and 58 mg of 10%palladium on carbon are added. The reaction mixture is agitated atambient temperature for 6 hours under an atmosphere of hydrogen atatmospheric pressure and is then filtered and concentrated under reducedpressure. The crude product is purified by silica gel chromatography ineluting with the aid of a dichloromethane/methanol mixture (97/3; v/v).The product sought after is thus obtained as a yellow pasty solid(yield=81%).

¹H NMR (300 MHz, DMSO) δ: 7.61 (d, 1H); 7.17 (dd, 1H); 6.80 (s, 2H);6.40 (dd, 1H); 5.43 (s, 2H); 4.11 (s, 2H); 3.79 (s, 3H); 3.55 (m, 4H);3.44 (m, 2H); 3.24 (t, 2H); 2.87 (m, 4H); 2.70 (s, 3H); 2.53 (s, 6H).

EXAMPLE 694-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(6-amino-3-pyridinyl)-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide,fumarate

In operating analogously to Example 4, starting with the compoundobtained following Example 68, the product sought after is obtained as abeige solid (yield=97%).

M.Pt.=194-196° C.

EXAMPLE 70N-[2-[2-[4-[2-(dimethylamino)-1,1-dimethylethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,trifluoroacetate

460 mg of polystyrene resin grafted with a cyclohexylcarbodiimidefunction are placed in 5 ml of DCM for 20 min. The solvent is removed byfiltration, and 100 mg (0.31 mM) of[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]aceticacid in solution in 3 ml of DCM, 37 mg (0.20 mM) of4-[2-(dimethylamino)-1,1-dimethylethyl]piperidine and 2 mg ofHOAT(1-hydroxy-7-azabenzotriazole), are then added. The mixture isagitated for 4 hours and then the resin is separated off by filtrationand rinsed with 4 ml of DCM. The combined organic phases are treatedwith 50 mg of Amberlite IRA 400 resin (OH⁻) for 3 hours, and then with100 mg of isocyanate grafted polystyrene resin for 1 hour. The resin isremoved by filtration and the filtrate is concentrated under reducedpressure. The product obtained is taken up into 0.5 ml of acetonitrileand 6 ml of a 1% solution of trifluoroacetic acid in water are added.The mixture is filtered and freeze-dried. 59 mg of the compound soughtafter are thus obtained as an amorphous solid (yield=48%).

M.Pt.=60° C.

¹H NMR (250 MHz, CD₃CN) δ: 6.74 (s, 2H); 4.50 (m, 1H); 4.06 (m, 2H);3.80 (s, 3H); 3.78 (m, 1H); 3.57 (t, 2H); 3.31 (t, 2H); 3.04 (s, 2H);2.85 (s, 6H); 2.83 (m, 1H); 2.73 (s, 3H); 2.56 (s, 6H); 2.55 (m, 1H);1.65 (m, 2H); 1.45 (m, 1H), 1.20 (m, 2H); 0.99 (s, 6H).

EXAMPLE 71N-[2-[2-[4-[2-(dimethylamino)-1-hydroxyethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,trifluoroacetate

In operating analogously to Example 70, starting with the compoundobtained according to preparation LXIX, the product sought after isobtained as a colourless paste (yield=45%).

¹H NMR (250 MHz, CD₃CN) δ: 6.74 (s, 2H); 4.45 (m, 1H); 4.05 (m, 2H);3.80 (s, 3H); 3.75 (m, 2H); 3.59 (t, 2H); 3.28 (t, 2H); 3.06 (m, 2H);2.90 (m, 1H); 2.84 (s, 3H); 2.80 (s, 3H); 2.77 (s, 3H); 2.56 (s, 6H);2.50 (m, 1H); 1.80 (m, 1H); 1.60 (m, 2H); 1.20 (m, 2H).

EXAMPLE 724-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

A suspension is prepared of 350 mg (1.06 mM) of acid obtained accordingto preparation III in 3 ml of DCM and 243 mg (1.27 mM) of EDCI(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and 173 mg(1.27 mM) of HOAT, are added. The mixture is agitated for 30 min atambient temperature, and 232 mg (1.27 mM) of1-methyl-4-(4-piperidinyl)piperazine are then added. The reactionmixture is agitated for 18 hours at ambient temperature and is thenpoured over 10 ml of water and extracted with DCM. The organic phase iswashed with water, dried and concentrated under reduced pressure. Theresidue is purified by silica gel chromatography in eluting with the aidof a DCM/methanol mixture (90/10; v/v). 449 mg of the product soughtafter are thus obtained as a yellow oil (yield=86%).

¹H NMR (300 MHz, CD₃CN) δ: 6.74 (s, 2H); 4.35 (d, 1H); 4.01 (q, 2H);3.81 (s, 3H); 3.69 (d, 1H); 3.56 (t, 2H); 3.26 (t, 2H); 2.89 (t, 1H);2.75 (s, 3H); 2.58 (s, 6H); 2.40 (m, 10H); 2.17 (s, 3H); 1.75 (m, 2H);1.27 (m, 2H).

EXAMPLE 734-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

404 mg (0.814 mM) of the compound obtained according to Example 72 aredissolved in 5 ml of methanol and 95 mg (0.815 mM) of fumaric acid areadded. The mixture is agitated for 10 min and then concentrated underreduced pressure. The residue is taken up into 10 ml of water and thesolution is freeze-dried. The salt sought after is thus obtained (474mg) as a white powder (yield=95%).

M.Pt.=90° C.

In operating analogously to Examples 72 and 73, starting with the acidsand the derivatives of piperidine described above or known from theliterature, the following compounds according to the invention areobtained:

EXAMPLE 744-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=44%).

M.Pt.=88-89° C.

EXAMPLE 75N-cyclopropyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=76%).

M.Pt.=148° C.

EXAMPLE 764-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=87%).

M.Pt.=55° C.

¹H NMR (300 MHz, CD3CN) δ: 8.50 (m broad, 1H); 6.74 (s, 2H); 4.38 (m,1H); 4.10 (d, 2H); 3.80 (s, 3H); 3.75 (m, 1H); 3.57 (m, 4H); 3.27 (t,2H); 3.13 (m, 2H); 2.95 (m, 3H); 2.74 (s, 3H); 2.57 (s, 6H); 2.50 (m,1H); 2.06 (m, 4H); 1.65 (m, 5H); 1.07 (m, 2H).

EXAMPLE 774-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[4-(1-methylethyl)-1-piperazinyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=92%).

M.Pt.=145° C.

EXAMPLE 78N-ethyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=50%).

M.Pt.=50° C.

EXAMPLE 79N-cyclopropyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=96%).

M.Pt.=50° C.

EXAMPLE 80N-[2-[2-[4-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=54%).

M.Pt.=60° C.

EXAMPLE 814-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-[methyl(1-methylethyl)amino]ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide,fumarate

White solid (yield=64%).

M.Pt.=60° C.

EXAMPLE 824-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[methyl(1-methyl-4-piperidinyl)amino]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=66%).

M.Pt.=72° C.

EXAMPLE 834-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1-(1-methylethyl)-4-piperidinyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=84%).

M.Pt.=62-64° C.

EXAMPLE 844-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-ethyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

Colourless oil (yield=35%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 6.51 (s, 2H); 4.32 (m, 1H); 4.06(q, 2H); 3.80 (s, 3H); 3.67 (m, 1H); 3.53 (m, 2H); 3.22 (m, 2H); 3.15(d, 2H); 2.86 (m, 1H); 2.69 (s, 3H); 2.61 (q, 2H); 2.53 (s, 6H); 2.45(m, 1H); 2.27 (t, 2H); 1.66 (m, 4H); 1.30 (m, 3H); 1.07 (t, 3H); 0.96(m, 3H).

EXAMPLE 854-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-cyclopropyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

Colourless oil (yield=63%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 6.66 (s, 2H); 4.34 (m, 1H); 4.01(q, 2H); 3.79 (s, 3H); 3.66 (m, 1H); 3.54 (t, 2H); 3.21 (t, 2H); 2.98(d, 2H); 2.82 (m, 1H); 2.69 (s, 3H); 2.53 (s, 6H); 2.43 (m, 1H); 2.10(t, 2H); 1.60 (m, 5H); 1.23 (m, 1H); 1.03 (m, 5H); 0.38 (m, 2H); 0.29(m, 2H).

EXAMPLE 864-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(4-morpholinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=73%).

M.Pt.=50° C.

EXAMPLE 874-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(1-azetidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=67%).

M.Pt.=60-62° C.

EXAMPLE 88N-ethyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=67%).

M.Pt.=65° C.

EXAMPLE 89N-[2-[2-[4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

Yellow oil (yield=61%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 6.50 (s, 2H); 4.36 (m, 1H); 4.11(m, 2H); 3.80 (s, 3H); 3.73 (m, 1H); 3.55 (t, 2H); 3.24 (t, 2H); 2.87(m, 2H); 2.85 (m, 6H); 2.69 (s, 3H); 2.67 (m, 1H); 2.53 (s, 6H); 2.46(s, 3H); 2.42 (m, 1H); 1.81 (m, 2H); 1.69 (m, 2H); 1.21 (m, 2H).

EXAMPLE 90N-cyclopropyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=60%).

M.Pt.=80° C.

EXAMPLE 912,4-dichloro-N,3-dimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=39%).

M.Pt.=86-88° C.

EXAMPLE 924-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(1-azetidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=40%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 6.52 (s, 2H); 4.28 (m, 1H); 4.05(m, 2H); 3.80 (s, 3H); 3.67 (m, 1H); 3.57 (m, 6H); 3.20 (t, 2H); 2.85(m, 1H); 2.78 (t, 2H); 2.69 (s, 3H); 2.53 (s, 6H); 2.49 (m, 1H); 2.17(quin, 2H); 1.59 (m, 2H); 1.50 (m, 1H); 1.30 (m, 2H); 0.93 (m, 2H).

EXAMPLE 932,6-dichloro-4-methoxy-N-methyl-N-[2-[2-[4-[2-(dimethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide,fumarate

White solid (yield=39%).

M.Pt.=70° C.

EXAMPLE 942,6-dichloro-4-methoxy-N-methyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=70%).

M.Pt.=67° C.

EXAMPLE 954-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(1-pyrrolidinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

Colourless oil (yield=30%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 6.54 (s, 2H); 4.29 (m, 1H); 4.15(m, 2H); 3.80 (s, 3H); 3.63 (m, 1H); 3.53 (t, 2H); 3.22 (t, 2H); 2.89(m, 1H); 2.80 (m, 4H); 2.70 (s, 3H); 2.56 (m, 1H); 2.53 (s, 6H); 2.51(m, 2H); 1.81 (m, 7H); 0.91 (m, 2H).

EXAMPLE 964-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(4-ethyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=31%).

M.Pt.=120° C.

EXAMPLE 97N-cyclopropyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-[(4-methyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=44%).

M.Pt.=160° C.

EXAMPLE 98N-ethyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-[(4-methyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=49%).

M.Pt.=98° C.

EXAMPLE 99N-methyl-4-methoxy-2,6-dichloro-N-[2-[2-[4-[(4-methyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=50%).

M.Pt.=103° C.

EXAMPLE 1004-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(1-piperidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,trifluoroacetate

Colourless oil (yield=47%).

¹H NMR (300 MHz, CD₃CN) δ: 7.50 (m broad, 1H); 6.74 (s, 2H); 4.49 (m,1H); 4.01 (q, 2H); 3.81 (s, 3H); 3.78 (m, 1H); 3.57 (t, 2H); 3.43 (m,2H); 3.28 (t, 2H); 3.01 (m, 2H); 2.98 (s, 2H); 2.90 (m, 1H); 2.74 (s,3H); 2.63 (s, 6H); 2.45 (m, 1H); 1.85 (m, 3H); 1.66 (m, 3H); 1.51 (m,2H); 1.19 (m, 3H); 1.00 (s, 6H).

EXAMPLE 1014-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=61%).

M.Pt.=50° C.

EXAMPLE 102N-[2-[2-[4-[2-(ethylmethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

White solid (yield=46%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 6.51 (s, 2H); 4.27 (m, 1H); 4.03(q, 2H); 3.80 (s, 3H); 3.55 (m, 1H); 3.24 (t, 2H); 3.22 (t, 2H); 2.86(m, 1H); 2.70 (s, 3H); 2.62 (m, 4H); 2.53 (s, 6H); 2.48 (m, 1H); 2.46(s, 3H); 1.66 (m, 2H); 1.52 (m, 1H); 1.45 (m, 2H); 1.38 (t, 3H); 0.97(m, 2H).

EXAMPLE 103N-[2-[2-[4-[2-(diethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate

White solid (yield=52%).

M.Pt.=60° C.

EXAMPLE 1044-methoxy-N-(1-methylethyl)-2,6-dimethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=61%).

M.Pt.=56° C.

EXAMPLE 1054-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(4-morpholinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White paste (yield=50%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 6.62 (s, 2H); 4.38 (m, 1H); 4.04(q, 2H); 3.79 (s, 3H); 3.55 (m, 1H); 3.52 (m, 6H); 3.21 (m, 2H); 2.81(m, 1H); 2.70 (s, 3H); 2.53 (s, 6H); 2.49 (m, 4H); 2.47 (m, 1H); 2.09(s, 2H); 1.60 (m, 2H); 1.43 (m, 1H); 1.10 (m, 2H); 0.76 (s, 6H).

EXAMPLE 106N-[2-[2-[4-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=36%).

M.Pt.=125° C.

EXAMPLE 107N-[2-[2-[4-[(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate

White solid (yield=31%).

M.Pt.=100-102° C.

EXAMPLE 1084-methoxy-N-[2-[2-[4-[2-(1-methyl-4-piperidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-N,2,6-trimethylbenzenesulphonamide,fumarate

White solid (yield=24%).

M.Pt.=70° C.

In operating analogously to Example 70, starting with the acids and thederivatives of piperidine described above or known from the literature,the following compounds according to the invention are obtained:

EXAMPLE 1094-methoxy-N-[2-[2-[4-[2-(1-piperidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-N,2,6-trimethylbenzenesulphonamide,fumarate

White solid (yield=69%).

M.Pt.=50° C.

EXAMPLE 1104-methoxy-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-N-methyl-2-trifluoromethyl-benzenesulphonamide,trifluoroacetate

Colourless oil (yield=99%).

¹H NMR (300 MHz, CD3CN) δ: 8.20 (m broad, 1H); 7.95 (d, 1H); 7.41 (d,1H); 7.25 (dd, 1H); 4.43 (m, 1H); 4.10 (q, 2H); 3.91 (s, 3H); 3.63 (m,1H); 3.63 (m, 4H); 3.43 (t, 2H); 3.13 (m, 2H); 2.96 (m, 2H); 2.90 (s,3H); 2.60 (t, 1H); 2.06 (m, 6H); 1.71 (m, 4H); 1.60 (m, 2H).

EXAMPLE 1114-methoxy-N-[2-[2-[4-[2-(1-methyl-4-piperazinyl)-2-oxoethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-N,2,6-trimethylbenzenesulphonamide,fumarate

White solid (yield=33%).

M.Pt.=60° C.

EXAMPLE 1124-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(diethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,trifluoroacetate

Colourless oil (yield=26%).

¹H NMR (300 MHz, DMSO) δ: 8.12 (m broad, 1H); 6.81 (s, 2H); 4.40 (m,1H); 4.09 (q, 2H); 3.80 (s, 3H); 3.78 (m, 1H); 3.54 (t, 2H); 3.24 (t,2H); 3.15 (m, 4H); 2.97 (d, 2H); 2.84 (t, 1H); 2.70 (s, 3H); 2.53 (s,6H); 2.41 (m, 1H); 1.64 (m, 2H); 1.42 (m, 1H); 1.25 (m, 2H); 1.22 (t,6H); 0.96 (s, 6H).

EXAMPLE 1134-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(dimethylamino)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=63%).

M.Pt.=65° C.

EXAMPLE 1144-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(1-azetidinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=60%).

M.Pt.=75° C.

EXAMPLE 115N,2,4,6-tetramethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,trifluoroacetate

Colourless oil (yield=97%).

¹H NMR (250 MHz, CD3CN) δ: 9.40 (m broad, 1H) 6.97 (s, 2H); 4.98 (m,1H); 4.09 (q, 2H); 3.71 (m, 1H); 3.57 (t, 2H); 3.45 (d, 2H); 3.28 (t,2H); 2.85 (m, 1H); 2.80 (m, 2H); 2.77 (s, 3H); 2.72 (d, 3H); 2.56 (s,6H); 2.45 (m, 1H); 2.28 (s, 3H); 1.92 (m, 2H); 1.71 (m, 2H); 1.50 (m,2H); 1.34 (m, 2H); 1.09 (m, 2H).

EXAMPLE 116N-methyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]-2-trifluoromethylbenzenesulphonamide,trifluoroacetate

Colourless oil (yield=98%).

¹H NMR (300 MHz, CD3CN) δ: 8.50 (m broad, 1H); 7.97 (m, 2H); 7.77 (m,2H); 4.48 (m, 1H); 4.13 (q, 2H); 3.80 (m, 1H); 3.64 (m, 2H); 3.49 (t,2H); 3.42 (m, 2H); 2.96 (s, 3H); 2.90 (m, 1H); 2.78 (m, 2H); 2.72 (d,3H); 2.50 (m, 1H); 1.93 (m, 2H); 1.73 (m, 2H); 1.38 (m, 4H); 1.36 (m,2H).

EXAMPLE 1174-methoxy-N-methyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]-2-trifluoromethylbenzenesulphonamide,trifluoroacetate

Colourless oil (yield=95%).

¹H NMR (300 MHz, CD3CN) δ: 8.41 (m broad, 1H); 7.96 (d, 1H); 7.40 (d,1H); 7.25 (dd, 1H); 4.45 (m, 1H); 4.10 (q, 2H); 3.91 (s, 3H); 3.80 (m,1H); 3.61 (t, 2H); 3.42 (m, 4H); 2.90 (s, 3H); 2.89 (m, 1H); 2.79 (m,2H); 2.73 (d, 3H); 2.50 (m, 1H); 1.92 (m, 2H); 1.73 (m, 2H); 1.37 (m,4H); 1.07 (m, 2H).

EXAMPLE 118N,2,4,6-tetramethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,trifluoroacetate

Colourless oil (yield=99%).

¹H NMR (300 MHz, CD3CN) δ: 8.40 (m broad, 1H); 7.03 (s, 2H); 4.37 (m,1H); 4.02 (q, 2H); 3.75 (m, 1H); 3.58 (m, 4H); 3.31 (t, 2H); 3.10 (m,2H); 2.91 (m, 3H); 2.75 (s, 3H); 2.56 (s, 6H); 2.54 (m, 1H); 2.29 (s,3H); 2.10 (m, 4H); 1.61 (m, 5H); 1.10 (m, 2H).

EXAMPLE 1192,6-dichloro-4-methoxy-N-methyl-N-[2-[2-[4-(1-methyl-4-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=76%).

M.Pt.=176° C.

EXAMPLE 1204-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(dimethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]-ethyl]benzenesulphonamide,fumarate

A solution is prepared of 200 mg (0.6 mM) of acid obtained according topreparation III in 2 ml of chloroform and 0.2 ml of dimethylformamideand 0.12 ml of oxalyl chloride are added at ambient temperature. Themixture is agitated for 1 hour at ambient temperature and concentratedunder reduced pressure. The residue is taken up into 3 ml of chloroform,and 103 mg (0.66 mM) of N,N-dimethyl-4-piperidineethanamine and 92 μl oftriethylamine are added, and agitation is carried out for 2 hours atambient temperature. The reaction mixture is concentrated under reducedpressure and the residue is purified by silica gel chromatography ineluting with the aid of a dichloromethane/methanol/aqueous ammoniamixture (95/5/0.5; v/v/v). 247 mg of amide are obtained as an oil whichis salified with fumaric acid according to the method applied in Example73 to obtain the salt as a white solid (yield=83%).

M.Pt.=55° C.

EXAMPLE 1214-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(4-cyclopropyl-1-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

2.2 g of tetrafluorophenol resin are placed in suspension in 10 ml ofdimethylformamide and 40 ml of dichloromethane and 50 mg of4-dimethylaminopyridine, 0.66 ml of diisopropylcarbodiimide and 1 g (3.1mM) of acid obtained according to preparation III, are added. Themixture is agitated at ambient temperature for 16 hours, and then theresin is separated off by filtration and reallowed to react in 40 ml ofdichloromethane with 0.5 g (2.39 mM) of1-cyclopropyl-4-(4-piperidinyl)piperazine, for 2 hours at ambienttemperature. The reaction mixture is filtered and the filtrate isconcentrated under reduced pressure. The crude product obtained ispurified by silica gel chromatography in eluting with the aid of adichloromethane/methanol mixture (99/1; v/v). 700 mg of amide areobtained as an oil which is salified with fumaric acid according to themethod applied in Example 73 to obtain the salt as a white solid(yield=49%).

M.Pt.=80° C.

In operating analogously to Example 121, starting with the aminesobtained according to preparations LXXXVIII and LXXIV, the followingcompounds according to the invention are obtained:

EXAMPLE 1224-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[4-(1,1-dimethylethyl)-1-piperazinyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=48%)

M.Pt.=170° C.

EXAMPLE 1234-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(4-methyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=39%)

M.Pt.=168° C.

In operating analogously to Examples 70 and 73, starting with the amineobtained according to preparation CVII, the following compound accordingto the invention is obtained

EXAMPLE 1244-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(4-methyl-1-piperazinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=59%)

M.Pt.=178-179° C.

PREPARATION CXLVII4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(3-hydroxypropyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

In operating analogously to Example 72, starting with3-(4-piperidinyl)propanol, the product sought after is obtained as acolourless oil (yield=79%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.34 (t, 1H); 4.28 (dm, 1H);4.03 (m, 2H); 3.79 (s, 3H); 3.64 (dm, 1H); 3.53 (t, 2H); 3.37 (d, 2H);3.21 (t, 2H); 2.86 (t, 1H); 2.70 (s, 3H); 2.53 (s, 6H); 2.45 (m, 1H);1.63 (d, 2H); 1.40 (m, 3H); 1.19 (m, 2H); 0.93 (m, 2H).

PREPARATION CXLVIII4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-[[(4-methylphenyl)sulphonyl]oxy]propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide

A solution is prepared of 6.8 g (14.9 mM) of the compound obtainedaccording to preparation CXLVII in 50 ml of dichloromethane and, atambient temperature, 3.4 ml (24.6 mM) of triethylamine, and then 4.68 g(24.6 mM) of tosyl chloride and 142 mg (1.5 mM) of trimethylaminehydrochloride, are added. The mixture is agitated for 4 hours underreflux of the solvent and then cooled and hydrolysed on 50 ml of water.The organic phase is washed with water, dried over magnesium sulphateand concentrated under reduced pressure. The residue is purified bysilica gel chromatography in eluting with the aid of an ethylacetate/toluene mixture (8/2; v/v). 5.6 g of the compound sought afterare obtained as a colourless oil (yield=62%).

¹H NMR (300 MHz, DMSO) δ: 7.79 (dd, 2H); 7.48 (d, 2H); 6.80 (s, 2H);4.26 (m, 1H); 4.00 (m, 3H); 3.79 (s, 3H); 3.62 (t, 2H); 3.51 (m, 2H);3.23 (m, 2H); 2.85 (m, 1H); 2.70 (s, 3H); 2.53 (s, 6H); 2.45 (m, 1H);2.41 (s, 3H); 1.55 (m, 3H); 1.29 (m, 2H); 1.13 (m, 2H); 0.89 (m, 2H).

EXAMPLE 1254-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(4-morpholinyl)-propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

A solution is prepared of 400 mg (0.65 mM) of the compound obtainedaccording to preparation CXLVIII in 8 ml of dimethylformamide and, atambient temperature, 90 mg (0.65 mM) of potassium carbonate, and then 95μl (1 mM) of morpholine, are added. The mixture is agitated for 16 hoursat 60° C. and then cooled, hydrolysed on 20 ml of water and extractedwith ethyl acetate. The organic phase is washed with water, dried overmagnesium sulphate and concentrated under reduced pressure. The residueis purified by silica gel chromatography in eluting with the aid of adichloromethane/methanol mixture (98/2; v/v). 150 mg of the compoundsought after are obtained as a colourless oil (yield=44%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.27 (m, 1H); 4.05 (q, 2H); 3.79(s, 3H); 3.70 (m, 1H); 3.54 (m, 6H); 3.21 (t, 2H); 2.85 (m, 1H); 2.70(s, 3H); 2.53 (s, 6H); 2.42 (m, 1H); 2.31 (m, 4H); 2.22 (t, 2H); 1.65(m, 2H); 1.41 (m, 3H); 1.36 (m, 2H); 0.96 (m, 2H).

EXAMPLE 1264-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(4-morpholinyl)-propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

In operating analogously to Example 73, starting with the compoundobtained according to Example 125, the product sought after is obtainedas a white solid (yield=99%).

M.Pt.=50° C.

In operating analogously to Examples 125 and 126, starting with variousamines, the following compounds according to the invention are obtained:

EXAMPLE 1274-methoxy-N,2,6-trimethyl-A[2-[2-[4-[3-(1-pyrrolidinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide

Colourless oil (yield=53%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.30 (m, 1H); 4.06 (q, 2H); 3.80(s, 3H); 3.68 (m, 1H); 3.53 (t, 2H); 3.20 (t, 2H); 2.90 (m, 1H); 2.71(s, 3H); 2.61 (m, 6H); 2.53 (s, 6H); 2.48 (m, 1H); 1.75 (s, 4H); 1.62(m, 2H); 1.48 (m, 2H); 1.42 (m, 1H); 1.21 (m, 2H); 0.92 (m, 2H).

EXAMPLE 1284-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(1-pyrrolidinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=92%).

M.Pt.=50° C.

EXAMPLE 1294-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

Colourless oil (yield=27%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.29 (m, 1H); 4.05 (q, 2H); 3.79(s, 3H); 3.65 (m, 1H); 3.50 (t, 2H); 3.23 (t, 2H); 2.85 (m, 1H); 2.69(s, 3H); 2.57 (m, 8H); 2.46 (t, 2H); 2.34 (s, 3H); 1.65 (m, 4H); 1.37(m, 3H); 1.17 (m, 2H); 0.95 (m, 2H).

EXAMPLE 1304-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=41%).

M.Pt.=174° C.

EXAMPLE 1314-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(4-methyl-1-piperazinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

Colourless oil (yield=43%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.27 (m, 1H); 4.03 (q, 2H); 3.79(s, 3H); 3.65 (m, 1H); 3.52 (t, 2H); 3.23 (t, 2H); 2.85 (m, 1H); 2.69(s, 3H); 2.53 (s, 6H); 2.48 (m, 1H); 2.29 (m, 8H); 2.23 (t, 2H); 2.12(s, 3H); 1.63 (m, 2H); 1.38 (m, 3H); 1.17 (m, 2H); 0.95 (m, 2H).

EXAMPLE 1324-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(4-methyl-1-piperazinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

White solid (yield=89%).

M.Pt.=174° C.

EXAMPLE 1334-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(1-azetidinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

Colourless oil (yield=23%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H), 4.26 (m, 1H); 4.02 (q, 2H); 3.80(s, 3H); 3.68 (m, 1H); 3.54 (t, 2H); 3.21 (t, 2H); 3.03 (t, 4H); 2.85(m, 1H); 2.70 (s, 3H); 2.53 (s, 6H); 2.48 (m, 2H); 2.47 (m, 1H); 2.25(t, 2H); 1.91 (quin, 2H); 1.60 (m, 2H); 1.40 (m, 1H); 1.18 (m, 4H); 0.89(m, 2H).

EXAMPLE 1344-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(1-azetidinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

White solid (yield=93%).

M.Pt.=65° C.

EXAMPLE 1354-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(dimethylamino)-propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

Colourless oil (yield=23%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.30 (m, 1H); 4.02 (q, 2H); 3.79(s, 3H); 3.65 (m, 1H); 3.52 (t, 2H); 3.21 (t, 2H); 2.85 (m, 1H); 2.70(s, 3H); 2.53 (s, 6H); 2.44 (m, 1H); 2.14 (t, 2H); 2.09 (s, 6H); 1.60(m, 2H); 1.38 (m, 3H); 1.17 (m, 2H); 0.91 (m, 2H).

EXAMPLE 1364-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(dimethylamino)-propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide,fumarate

White solid (yield=99%).

M.Pt.=55° C.

PREPARATION CIL1′-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl][4,4′-bipiperidine]-1-carboxylicacid, 1,1-dimethylethyl ester

In operating analogously to Example 72, starting with the compoundobtained according to preparation LXXXIX, the product sought after isobtained as a colourless oil (yield=88%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.39 (m, 1H); 3.98 (m, 4H); 3.79(s, 3H); 3.70 (m, 1H); 3.53 (t, 2H); 3.20 (t, 2H); 2.85 (m, 1H); 2.69(s, 3H); 2.61 (m, 2H); 2.53 (s, 6H); 2.43 (m, 1H); 1.62 (m, 4H); 1.38(s, 9H); 1.23 (m, 2H); 1.01 (m, 4H).

EXAMPLE 137N-[2-(2-[4,4′-bipiperidin]-1-yl-2-oxoethoxy)ethyl]-4-methoxy-N,2,6-trimethyl-benzenesulphonamide,trifluoroacetate

In operating analogously to preparation CXXI, starting with the compoundobtained according to preparation CIL, the product sought after isobtained as a white foam (yield=99%).

¹H NMR (250 MHz, CD3CN) δ: 7.00 (m broad, 1H); 6.74 (s, 2H); 4.48 (m,1H); 4.05 (q, 2H); 3.80 (s, 3H); 3.75 (m, 1H); 3.57 (t, 2H); 3.35 (m,2H); 3.30 (t, 2H), 2.92 (m, 3H); 2.74 (s, 3H); 2.57 (s, 6H); 2.48 (m,1H); 1.89 (m, 2H); 1.71 (m, 2H); 1.43 (m, 4H); 1.10 (m, 2H).

PREPARATION CL[2-[1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-4-piperidinyl]ethyl]methyl-carbamicacid, 1,1-dimethylethyl ester

In operating analogously to Example 72, starting with the compoundobtained according to preparation CXIV, the product sought after isobtained as a colourless oil (yield=82%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.32 (m, 1H); 4.04 (q, 2H); 3.80(s, 3H); 3.69 (m, 1H); 3.56 (t, 2H); 3.21 (t, 2H); 3.19 (m, 2H); 2.85(m, 1H); 2.74 (s, 3H); 2.70 (s, 3H); 2.53 (s, 6H); 2.46 (m, 1H); 1.65(m, 2H); 1.38 (s, 9H); 1.34 (m, 3H); 1.01 (m, 2H).

EXAMPLE 1384-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(methylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

In operating analogously to preparation XXIX, starting with the compoundobtained according to preparation CL, the product sought after isobtained as a colourless oil (yield=99%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.25 (m, 1H); 4.05 (q, 2H); 3.80(s, 3H); 3.65 (m, 1H); 3.55 (t, 2H); 3.19 (t, 2H); 2.85 (m, 1H); 2.70(s, 3H); 2.51 (s, 6H); 2.48 (m, 3H); 2.24 (s, 3H); 1.59 (m, 2H); is 1.52(m, 1H); 1.34 (m, 2H); 0.92 (m, 2H).

EXAMPLE 1394-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(methylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate

In operating analogously to Example 73, starting with the compoundobtained according to Example 138, the product sought after is obtainedas a white solid (yield=99%).

M.Pt.=50° C.

PREPARATION CLI[1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-4-piperidinyl]carbamicacid, 1,1-dimethylethyl ester

In operating analogously to Example 72, starting witht-butyl(4-piperidinyl)carbamate, the product sought after is obtained asa colourless oil (yield=66%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.07 (m, 1H); 4.04 (m, 2H); 3.80(s, 3H); 3.52 (m, 4H); 3.22 (t, 2H); 2.95 (m, 1H); 2.70 (s, 3H); 2.67(m, 1H); 2.53 (s, 6H); 1.72 (m, 2H); 1.38 (s, 9H); 1.26 (m, 2H).

EXAMPLE 140N-[2-[2-(4-amino-1-piperidinyl)-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethyl-benzenesulphonamide

In operating analogously to preparation XXIX, starting with the compoundobtained according to preparation CL, the product sought after isobtained as a yellow oil (yield=86%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.13 (m, 1H); 4.05 (m, 2H); 3.80(s, 3H); 3.60 (m, 1H); 3.55 (t, 2H); 3.46 (m broad, 2H); 3.22 (t, 2H);2.89 (m, 2H); 2.70 (s, 3H); 2.67 (m, 1H); 2.53 (s, 6H); 1.74 (m, 2H);1.51 (m, 2H).

EXAMPLE 1414-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

In operating analogously to preparation LXXI, starting with the compoundobtained according to Example 140, the product sought after is obtainedas a colourless oil (yield=40%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.13 (m, 1H); 4.05 (m, 2H); 3.79(s, 3H); 3.65 (m, 1H); 3.50 (t, 2H); 3.22 (t, 2H); 2.91 (m, 4H); 2.70(s, 3H); 2.60 (m, 2H); 2.51 (s, 6H); 1.85 (m, 8H); 1.45 (m, 2H); 0.96(m, 2H).

EXAMPLE 1424-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-1-piperidinyl]-2-oxoethoxy]-ethyl]benzenesulphonamide,bis(trifluoroacetate)

A mixture of 140 mg (0.26 mM) of the compound obtained according toExample 141 is agitated until dissolution in 4 ml of a solution of 6%trifluoroacetic acid in water. The solution is frozen and freeze-driedand 200 mg of the product sought after are thus obtained as a whitesolid (quantitative yield).

M.Pt.=70° C.

In operating analogously to preparation CLI and to Examples 140 to 142,starting with t-butyl methyl(4-piperidinyl)carbamate, the followingcompounds are obtained:

PREPARATION CLII[1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-4-piperidinyl]methylcarbamicacid, 1,1-dimethylethyl ester

Colourless oil (yield=49%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.38 (m, 1H); 4.32 (m, 1H); 4.07(m, 2H); 4.01 (m, 1H); 3.80 (s, 3H); 3.74 (m, 1H); 3.54 (m, 2H); 3.23(t, 2H); 2.93 (m, 1H); 2.70 (s, 3H); 2.63 (s, 3H); 2.53 (s, 6H); 1.53(m, 4H); 1.39 (s, 9H).

EXAMPLE 1434-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(methylamino)-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide

Colourless oil (yield=99%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.18 (m, 1H); 4.08 (m, 2H); 3.80(s, 3H); 3.68 (m, 1H); 3.54 (t, 2H); 3.23 (t, 2H); 2.95 (m, 1H); 2.85(m, 1H); 2.70 (s, 3H); 2.67 (m, 1H); 2.53 (s, 6H); 2.42 (s, 3H); 1.85(m, 2H); 1.25 (m, 2H).

EXAMPLE 1444-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[methyl(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

Colourless oil (yield=34%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.30 (m, 1H); 4.10 (q, 2H); 3.80(s, 3H); 3.67 (m, 1H); 3.52 (t, 2H); 3.30 (m, 2H); 3.21 (t, 2H); 2.88(m, 1H); 2.75 (m, 2H); 2.70 (s, 3H); 2.53 (s, 6H); 2.49 (m, 1H); 2.14(s, 3H); 2.05 (s, 3H); 1.89 (m, 2H); 1.45 (m, 8H); 1.23 (m, 2H).

EXAMPLE 1454-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[methyl(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,bis(trifluoroacetate)

Colourless oil (yield=99%).

¹H NMR (250 MHz, CD3CN) δ: 6.75 (s, 2H); 4.62 (m, 1H); 4.06 (m, 2H);3.97 (m, 2H); 3.92 (m, 1H); 3.81 (s, 3H); 3.65 (m, 1H); 3.59 (m, 3H);3.30 (t, 2H); 3.05 (m, 1H); 2.74 (s, 3H); 2.71 (d, 3H); 2.63 (s, 3H);2.70-2.55 (m, 3H); 2.53 (s, 6H); 2.27 (m, 4H); 1.97 (m, 4H); 1.62 (m,2H).

PREPARATION CLIII4-[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]methyl]-1-piperazinecarboxylicacid, phenylmethyl ester

In operating analogously to preparation LXXI, starting with the t-butylester of 4-formyl-1-piperidinecarboxylic acid and with the benzyl esterof 1-piperazinecarboxylic acid, the product sought after is obtained asa colourless oil (yield=26%).

¹H NMR (300 MHz, DMSO) δ: 7.31 (m, 5H); 5.11 (s, 2H); 3.90 (m, 2H); 3.64(m, 4H); 2.75 (m, 8H); 1.89 (m, 1H); 1.70 (m, 2H); 1.39 (s, 9H); 1.04(m, 2H).

PREPARATION CLIV 4-(4-piperidinylmethyl)-1-piperazinecarboxylic acid,phenylmethyl ester

In operating analogously to preparation XXIX, starting with the compoundobtained according to preparation CLIII, the product sought after isobtained as a colourless oil (yield=83%).

¹H NMR (250 MHz, DMSO) δ: 7.35 (m, 5H); 5.00 (s, 2H); 3.35 (m, 4H); 2.95(m, 2H); 2.46 (m, 2H); 2.30 (m, 4H); 2.11 (m, 2H); 1.65 (m, 3H); 0.98(m, 2H).

PREPARATION CLV4-[[1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-4-piperidinyl]methyl]-1-piperazinecarboxylicacid, phenylmethyl ester

In operating analogously to Example 72, starting with the compoundobtained according to preparation CLIV, the product sought after isobtained as a colourless oil (yield=70%).

¹H NMR (250 MHz, DMSO) δ: 7.35 (m, 5H); 6.80 (s, 2H); 5.07 (s, 2H); 4.25(m, 1H); 4.05 (m, 2H); 3.79 (s, 3H); 3.68 (m, 1H); 3.53 (t, 2H); 3.30(m, 4H); 3.21 (t, 2H); 2.88 (m, 1H); 2.69 (s, 3H); 2.53 (s, 6H); 2.51(m, 1H); 2.31 (m, 4H); 2.27 (m, 2H); 1.70 (m, 3H); 0.95 (m, 2H).

EXAMPLE 1464-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(1-piperazinyl-methyl)-1-piperidinyl]ethoxy]ethyl]benzenesulphonamide

In operating analogously to preparation XXXV, starting with the compoundobtained according to preparation CLV, the product sought after isobtained as a colourless oil (yield=93%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.25 (m, 1H); 4.05 (q, 2H); 3.79(s, 3H); 3.54 (m, 1H); 3.51 (t, 2H); 3.23 (t, 2H); 2.87 (m, 1H); 2.70(s, 3H); 2.66 (m, 4H); 2.53 (s, 6H); 2.50 (m, 1H); 2.46 (m, 4H); 2.05(d, 2H); 1.74 (m, 3H); 0.98 (m, 2H).

EXAMPLE 1474-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(1-piperazinyl-methyl)-1-piperidinyl]ethoxy]ethyl]benzenesulphonamide,fumarate

In operating analogously to Example 73, starting with the compoundobtained according to Example 146, the product sought after is obtainedas a white solid (yield=93%).

M.Pt.=85-87° C.

PREPARATION CLVI1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-4-piperidinecarboxylicacid, ethyl ester

In operating analogously to Example 70, starting with the ethyl ester of4-piperidinecarboxylic acid, the product sought after is obtained as acolourless oil (yield=89%).

¹H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 4.17 (m, 5H); 3.80 (s, 3H); 3.65(m, 1H); 3.53 (t, 2H); 3.29 (s, 3H); 3.21 (t, 2H); 2.99 (m, 1H); 2.72(m, 1H); 2.70 (s, 3H); 2.58 (m, 1H); 2.53 (s, 6H); 1.83 (m, 2H); 1.44(m, 2H); 1.20 (t, 3H).

PREPARATION CLVII1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-4-piperidinecarboxylicacid

A solution is prepared of 2.3 g (4.89 mM) of ester obtained according topreparation CLVI in 40 ml of tetrahydrofuran and a solution of 246 mg(5.8 mM) of lithia in 3 ml of water is added. The mixture is agitated atambient temperature overnight and then concentrated under reducedpressure. The residue is taken up into 25 ml of water, acidified up topH 2 with an N solution of hydrochloric acid and extracted with ethylacetate. The organic phase is dried over magnesium sulphate andconcentrated under reduced pressure. The crude product is purified bysilica gel chromatography in eluting with the aid of adichloromethane/methanol mixture (95/5; v/v). 1.6 g of the compoundsought after are obtained as a colourless oil (yield=74%).

¹H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.10 (m, 1H); 4.06 (m, 2H); 3.79(s, 3H); 3.55 (m, 1H); 3.53 (t, 2H); 3.23 (t, 2H); 2.98 (m, 1H); 2.74(m, 1H); 2.70 (s, 3H); 2.53 (s, 3H); 2.50 (s, 6H); 2.43 (m, 1H); 1.85(m, 2H); 1.40 (m, 2H).

EXAMPLE 1484-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-[1-oxo-2-(4-methyl-1-piperazinyl)ethyl]-1-piperidinyl]ethoxy]-ethyl]benzenesulphonamide,bis(trifluoroacetate)

A solution is prepared of 0.65 g (1.47 mM) of acid obtained according topreparation CLVII in 20 ml of dichloromethane and 0.25 ml of oxalylchloride are added. The mixture is agitated for 2 hours at ambienttemperature and is concentrated under reduced pressure. The yellow oilobtained is taken up into 8 ml of tetrahydrofuran and 8 ml ofacetonitrile and, at 0° C., 0.74 ml (1.47 mM) of a 2M solution oftrimethylsilyldiazomethane in hexane are added. The mixture is agitated1 hour at ambient temperature and then concentrated under reducedpressure. The residue is taken up into solution in 10 ml of chloroformand is added dropwise to a solution of 147 mg (1.47 mM) ofN-methylpiperazine in 10 ml of chloroform, in the presence of 10 mg ofchlorocyclopentadienylbis(triphenylphosphine)ruthenium(II), at 60° C.The reaction mixture is agitated at 60° C. for 30 min and thenconcentrated under reduced pressure. The crude product is purified bysilica gel chromatography in eluting with the aid of adichloromethane/methanol mixture (85/15; v/v). The oily product obtainedis salified directly trifluoroacetic acid in applylng the proceduredescribed in Example 142. 0.167 g of the compound sought after areobtained as a colourless oil (yield=21%).

¹H NMR (300 MHz, CD3CN) δ: 6.75 (s, 2H); 4.35 (m, 1H); 4.04 (m, 2H);3.83 (s, 3H); 3.81 (s, 2H); 3.70 (m, 1H); 3.58 (t, 2H); 3.38 (m, 4H);3.30 (t, 2H); 3.22 (m, 4H); 2.95 (m, 1H); 2.81 (s, 3H); 2.74 (s, 3H);2.69 (m, 2H); 2.56 (s, 6H); 1.80 (m, 2H); 1.45 (m, 2H).

EXAMPLE 1494-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)]-1-piperazinyl]-2-oxoethoxy]ethyl]benzenesulphonamide

A solution is prepared of 7 g (21 mM) of acid obtained according topreparation III in 50 ml of chloroform and 0.1 ml of dimethylformamideand, at ambient temperature, a solution of 3.7 ml (42 mM) of oxalylchloride in 8 ml of chloroform, is added dropwise. The reaction mixtureis agitated for 3 hours at ambient temperature and concentrated underreduced pressure. The residue from evaporation is taken up into 20 ml ofchloroform and is added slowly, at 0° C., to a solution of 4.04 g (22mM) of 1-(1-methyl-4-piperidinyl)piperazine and 8.7 ml of triethylaminein 40 ml of chloroform. The reaction mixture is agitated for 1 hour at0° C. and then poured over 60 ml of iced water. The mixture obtained isextracted with 100 ml of chloroform and the organic phase is washed witha solution of sodium bicarbonate, and then with water, dried overmagnesium sulphate and concentrated under reduced pressure. The productsought after is thus obtained as an oil (yield=81.7%) which is used,without other purification, to obtain a salt with an acid.

EXAMPLE 1504-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)]-1-piperazinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,dihydrochloride

A solution is prepared of 6 g (12 mM) of the compound obtained accordingto Example 149 in 100 ml of ethanol heated to around 65° C. 3.2 ml (36mM) of concentrated hydrochloric acid are then added, at around 60° C. Aprecipitate forms rapidly. After 2 hours under agitation at ambienttemperature, the suspension is cooled to 0° C. and filtered on a sinter.The solid isolated is washed with 10 ml of cold ethanol and then with 15ml of ethyl ether and dried under reduced pressure. 5.2 g of the saltsought after are thus obtained as a white solid (yield=75%).

M.Pt.>250° C.

EXAMPLE 1514-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)]-1-piperazinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate

In operating analogously to Example 150, with 2.5 equivalents of fumaricacid, the product sought after is obtained as a white solid (yield=76%).

M.Pt.=185° C.

TABLE I

EX R₁ R₂ R₃(R₄) R_(a) X p A B Salt 1 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₂

2TFA 2 4-CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2TFA 3 4-CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

— 4 4-CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2F 5 4-CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

— 6 4-CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

1F 7 4-CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

1F 8 4-CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₃

2TFA 9 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₂

2TFA 10 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₂

2TFA 11 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₃

2TFA 12 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₃ —N(CH₃)₂ 2TFA 13 4-O—CH₃2-CH₃ 6-CH₃ —CH₃ N 2 Is

2TFA 14 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

1F 15 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 3 Is

1F 16 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₃

2F 17 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2F 18 4-O—CH₃ 2-CH₃ 6-CH₃ c-Pr N 2 Is

2F 19 4-O—CH₃ 2-CH₃ 6-CH₃ c-Pr N 2 (CH₂)₂

2F 20 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 —CH₂—

2F 21 4-O—CH₃ 2-CH₃ 6-CH₃ —C₂H₅ N 2 Is

2F 22 4-O—CH₃ 2-CH₃ 6-CH₃ —C₂H₅ N 2 (CH₂)₃ —N(CH₃)₂ 2F 23 4-O—CH₃ 2-CH₃6-CH₃ —CH₃ N 2 Is

1F 24 4-O—CH₃ 2-CH₃ 6-CH₃ —C₂H₅ N 2 (CH₂)₃

2F 25 4-O—CH₃ 2-CH₃ 6-CH₃ c-Pr N 2 (CH₂)₃

2F 26 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

1F 27 4-O—CH₃ 2-CH₃ 6-CH₃ —C₂H₅ N 2 Is

2F 28 4-O—CH₃ 2-CH₃ 6-CH₃ c-Pr N 2 Is

2F 29 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2F 30 4-O—CH₃ 2-CH₃ 6-CH₃ i-Pr N 2 Is

2F 31 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

1F 32 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2F 33 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 —CH₂—

1F 34 4-O—CH₃ 2-Cl 6-Cl —CH₃ N 2 —(CH₂)₃— —N(CH₃)₂ 2F 35 4-O—CH₃ 2-Cl6-Cl —CH₃ N 2 Is

2F 36 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 —(CH₂)₂—

2F 37 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

1F 38 4-O—CH₃ 2-CH₃ 6-CH₃ i-Pr N 2 Is

2F 39 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

1F 40 4-O—CH₃ 2-CH₃ 6-CH₃ —C₂H₅ N 2 (CH₂)₃

2F 41 4-Cl 2-Cl 6-O—CH₃ —CH₃ N 2 Is

2F 42 4-O—CH₃ 2-Cl 6-Cl —CH₃ N 2 Is

1F 43 4-O—CH₃ 2-Cl 6-Cl —CH₃ N 2 Is

1F 44 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2TFA 45 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₃

2F 46 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2F 47 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₃

2F 48 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2F 49 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 —(CH₂)₂—CO—

2TFA 50 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₂

3F 51 4-O—CH₃ 2-CH₃ 6-CH₃ c-Pr N 2 Is

2F 52 4-O—CH₃ 2-CH₃ 6-CH₃ —C₂H₅ N 2 Is

2F 53 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₂ —N(C₂H₅)₂ 1F 54 4-F 2-Cl 6-Cl—CH₃ N 2 Is

base 55 4-F 2-Cl 6-Cl —CH₃ N 2 Is

2F 56 4-Br 2-Cl 6-Cl —CH₃ N 2 Is

base 57 4-Br 2-Cl 6-Cl —CH₃ N 2 Is

2F 58 4-Cl 2-Cl 6-Cl —CH₃ N 2 Is

base 59 4-Cl 2-Cl 6-Cl —CH₃ N 2 Is

2F 60 4-Cl 2-Cl 6-CH₃ —CH₃ N 2 Is

base 61 4-Cl 2-Cl 6-CH₃ —CH₃ N 2 Is

2F 62 4-O—CH₃ 2-CH₃ 3,6-diCH₃ —CH₃ N 2 Is

base 63 4-O—CH₃ 2-CH₃ 3,6-diCH₃ —CH₃ N 2 Is

2F 64 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₃

base 65 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₃

base 66 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 (CH₂)₃

2F 67 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2TFA 68 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

base 69 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

1F 70 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —C(CH₃)₂—CH₂— —N(CH₃)₂ 1TFA 714-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH(OH)—CH₂— —N(CH₃)₂ 1TFA 72 4-O—CH₃2-CH₃ 6-CH₃ —CH₃ CH 2 Is

base 73 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1F 74 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1F 75 4-O—CH₃ 2-CH₃ 6-CH₃ CPr CH 2 Is

2F 76 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

1F 77 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1F 78 4-O—CH₃ 2-CH₃ 6-CH₃ —C₂H₅ CH 2 (CH₂)₂

1F 79 4-O—CH₃ 2-CH₃ 6-CH₃ cPr CH 2 (CH₂)₂

1F 80 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

2F 81 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

1F 82 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —N(CH₃)—

1F 83 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1F 84 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1F 85 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1F 86 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

1F 87 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —C(CH₃)₂—CH₂—

1F 88 4-O—CH₃ 2-CH₃ 6-CH₃ —C₂H₅ CH 2 Is

1F 89 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1F 90 4-O—CH₃ 2-CH₃ 6-CH₃ cPr CH 2 Is

1F 91 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1F 92 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —(CH₂)₂—

1F 93 4-O—CH₃ 2-Cl 6-Cl —CH₃ CH 2 (CH₂)₂ —N(CH₃)₂ 1F 94 4-O—CH₃ 2-Cl6-Cl —CH₃ CH 2 Is

1F 95 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH_(2—)

1F 96 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH_(2—)

1F 97 4-O—CH₃ 2-CH₃ 6-CH₃ cPr CH 2 —CH_(2—)

2F 98 4-O—CH₃ 2-CH₃ 6-CH₃ —C₂H₅ CH 2 —CH_(2—)

2F 99 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH_(2—)

2F 100 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —C(CH₃)₂'CH₂—

1TFA 101 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —C(CH₃)₂'CH₂—

1F 102 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

1F 103 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂ —N(C₂H₅)₂ 1F 104 4-O—CH₃2-CH₃ 6-CH₃ iPr CH 2 (CH₂)₂

1F 105 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —C(CH₃)₂—CH₂—

1F 106 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

2F 107 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH₂—

2F 108 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

1F 109 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

1F 110 4-O—CH₃ 2-CF₃ H —CH₃ CH 2 (CH₂)₂

1TFA 111 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH₂—CO—

1F 112 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —C(CH₃)₂—CH₂— —N(C₂H₅)₂ 1TFA 1134-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH₂— —N(CH₃)₂ 1F 114 4-O—CH₃ 2-CH₃ 6-CH₃—CH₃ CH 2 —CH₂—

1F 115 4-CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1TFA 116 H 2-CF₃ H —CH₃ CH 2 Is

1TFA 117 4-O—CH₃ 2-CF₃ H —CH₃ CH 2 Is

1TFA 118 4-CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

1TFA 119 4-O—CH₃ 2-Cl 6-Cl —CH₃ CH 2 Is

2F 120 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂ —N(CH₃)₂ 1F 121 4-O—CH₃2-CH₃ 6-CH₃ —CH₃ CH 2 Is

1F 122 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is

2F 123 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH₂—

2F 124 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂

2F 125 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

base 126 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

1F 127 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

base 128 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

1F 129 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

base 130 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

2F 131 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

base 132 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

2F 133 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

base 134 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃

1F 135 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃ —N(CH₃)₂ base 136 4-O—CH₃2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₃ N(CH₃)₂ 1F 137 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH2 Is

1FTA 138 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂ —NH(CH₃) Base 139 4-O—CH₃2-CH₃ 6-CH₃ —CH₃ CH 2 (CH₂)₂ —NH(CH₃) 1F 140 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH2 Is —NH₂ base 141 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —NH—

base 142 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —NH—

2TFA 143 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 Is —NH(CH₃) base 144 4-O—CH₃2-CH₃ 6-CH₃ —CH₃ CH 2 —N(CH₃)—

base 145 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —N(CH₃)—

2TFA 146 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH₂—

base 147 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CH₂—

1F 148 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ CH 2 —CO—CH₂—

2TFA 149 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

base 150 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2HCl 151 4-O—CH₃ 2-CH₃ 6-CH₃ —CH₃ N 2 Is

2F

In the above table, Is means a single bond, TFA means that the compoundis in the form of a salt with trifluoroacetic acid, F means that thecompound is in the form of a salt with fumaric acid. HCl means that thecompound is in the form of a salt with hydrochloric acid.

Biological Activity

The compounds of the present invention were evaluated for theiranalgesic property using the formalin-induced pain response test in mice(Shibata, M., Ohkubo, T., Takahashi, H. & R. Inoki. Modified formalintest: characteristic biphasic pain response. Pain, 38, 347-352). Tosummarize, formalin (0.92% in physiological saline) is injected into thehind paw and the period of paw licking, which represents pain intensity,is recorded from 0 to 5 min (1^(st) phase) and from 15 to 30 min (2^(nd)phase) after the injection. According to this test, the percentageinhibition of the second paw licking phase induced by formalin is 43%for the compound of example 4 administered via the oral route at a doseof 3 mg/kg and 40% for the compound of example 6 administered via theoral route at a dose of 1 mg/kg.

These results demonstrate a substantial lowering of pain response afteradministering the compounds.

Subsequent to the results of the preceding test, the compounds of theinvention were subjected to a test intended to demonstrate their mode ofaction and involving the B₁ receptor of bradykinin.

This test uses the human umbilical vein and is conducted as per thefollowing protocol:

Human umbilical cords 15-25 cm long are recovered just after deliveryand are immediately placed in a flask containing a Krebs solution ofcomposition (in mM): 119 NaCl 119, 4.7 KCl, 1.18 KH₂PO₄, 1.17 MgSO₄, 25NaHCO₃, 2.5 CaCl₂, 5.5 Glucose, 0.026 EDTA then stored at 4° C.

The cord is dissected in Krebs solution to release the umbilical vein.The vein is cleansed of all adhering tissue and cut into small rings 3-4mm in width. The endothelium is carefully removed by inserting a fine n°1 catheter, made slightly abrasive, into the vessel lumen.

To induce expression of the B₁ receptor of bradykinin, the vein segmentsare allowed to incubate at 37° C. in a 25 ml chamber for 16 hours in anEMEM culture medium oxygenated by a 95% O₂+5% CO₂ mixture to whichantibiotics are added: penicillin 10 000 IU/ml and streptomycin 10 000IU/ml. The following day, the vein rings are mounted on a stainlesssteel support connected to an isometric sensor and placed in a 8 mlisolated organ bath chamber thermostated at 37° C., containing the Krebssolution oxygenated by a 95% O₂+5% CO₂ mixture.

After a rest period of one hour during which the rings are rinsed 5 to 6times with the Krebs solution (maintained at 37° C. throughout theentire handling procedure and oxygenated by a 95% O₂+5% CO₂ mixture),the vein is gradually subjected to a 1 g load. When the load is stable,after approximately 45 minutes, the Krebs solution is replaced by ahyper-potassium solution (KPSS: at a temperature of 37° C.) of the samecomposition but containing 125 mM KCl and not NaCl.

After a series of rinsings, rests and load readjustments, the maximumcontraction of each segment is determined by further depolarisation withthe KPSS solution.

After a new rest period during which the 1 g load is constantlyreadjusted, the following compounds are added to the isolated organbath: Mepyramine (1 μM), Atropine (1 μM), Indometacine (3 μM), LNA (30μM), Captopril (10 μM), DL-Thiorphan (1 μM) and Nifedipine (0.1 μM).

After 20 minutes, the molecule to be tested or the molecule solvent isadded to the isolated organ bath. The molecules are examined at 10 μM;should a molecule show a sufficient level of activity, it is examined atlower concentrations (eg: 1-0.1-0.01 μM).

After 15 minutes incubation, the vein segments are contracted throughthe addition of increasing concentrations of des-Arg10-Kallidin (0.1 nMto 30 000 nM) in the chamber.

The EC₅₀ values (effective concentrations of agonists required toproduce 50% of the maximum response obtained with KPSS) are calculatedusing the least square method.

The pK_(B)=[−log K_(B)] is obtained from the equation:K _(B) —[A]/(concentration ratio−1)in which [A] is the concentration of antagonist and the (concentrationratio) represents the ratio between EC₅₀ in the presence of anantagonist and EC₅₀ in the absence of antagonist.

According to this test, the compounds of the invention cited in thedescription show a pK_(B) value of more than 7.

By way of example, the pK_(B) values of some compounds of the inventionare given in table II:

Ex. 13 19 21 32 33 45 46 74 76 77 79 84 89 99 120 pK_(B) 8.4 7.5 7.8 9.28.6 7.9 8.6 9 8 8.5 8.1 9.2 8.1 8 7.6

The compounds of the present invention may be used to treat variousforms of pain such as inflammatory hyperalgesia, allodynia, neuropathicpain assoicated with, for example, diabetes, with neuropathies(constriction of sciatica nerve, lumbago), with any form of trauma,surgery (tooth extraction, tonsil removal), interstitial cystitis,inflammatory colon disease, or with cancer.

The compounds of the present invention may also be used to treat anypathology associated with neutrophil migration such as acute respiratorydistress syndrome for example, or psoriasis, chronic lung obstructions,inflammatory diseases, in particular inflammatory diseases of the colon,rheumatoid polyarthritis.

The activity of the compounds of the invention, evidenced during thebiological tests, is indicative of analgesic properties and permitstheir considered use for therapy.

According to the invention, the use is advocated of compounds defined byformula I and of their salts with non-toxic acids, preferably theirpharmaceutically acceptable salts, as active ingredients in medicinalproducts intended for the treatment of mammals, notably in man,suffering from pain or certain diseases generally characterized bymassive neutrophil migration.

Among the diseases which can be treated by administering atherapeutically efficient quantity of at least one of the formula Icompounds, mention may be made of inflammatory hyperalgesia, neuropathicpain, pain assoicated with trauma or with cancer, inflammatory diseasesof the colon, rheumatoid polyarthritis, psoriasis, chronic lungobstructions or acute respiratory distress syndrome.

The invention also concerns a method for treating pain or theabove-mentioned diseases which consists of administering atherapeutically efficient quantity of a formula I compound to patientsin need thereof.

The dose of active ingredient is dependent upon the mode ofadministration and type of pathology; it is generally between 0.05 and10 mg/kg of the treated patient. In relation to the intended treatment,the formula I compounds or their salts may be associated with otheractive ingredients and are to be formulated with routinely usedexcipients.

To obtain swift action, notably for the treatment of acute pain, themethod of administration of the medicinal product is preferably byinjection, for example via the intramuscular or the subcutaneous route.For chronic pain, the medicinal product may be administered in commongalenic formulations, for example via the oral route in capsule ortablet form, in which a compound of the invention is associated withexcipients known to persons skilled in the art, or in adhesive patchform in which a compound of the invention is formulated with excipientsknown to persons skilled in the art to promote transdermal passing ofthe active ingredient.

1. A compound, selected from the group consisting of: a) a compound offormula:

in which, R₁ represent a hydrogen, a halogen, a C₁-C₃ alkyl group, or aC₁-C₃ alkoxy group, R₂ represents a hydrogen, a halogen, a C₁-C₃ alkylgroup, a C₁-C₃ alkoxy group, or a CF₃ groups, R₃ represents a hydrogen,a halogen, a C₁-C₃ alkyl group or a C₁-C₃ alkoxy group, R₄ represents ahydrogen or a C₁-C₃ alkyl group, R_(a) represents a C₁-C₄ alkyl group, Yrepresents a —CH₂—CH₂—O—CH₂— group, X represents CH or a nitrogen atom,p represents 2 or 3, A represents a single bond, a nitrogen atomoptionally substituted with a methyl group, or a straight or branchedC₁-C₅ alkylene group optionally hydroxylated or of which one of thecarbon atoms is oxidized into a ketone function, provided that A and Xtogether do not represent a nitrogen atom, B represents anitrogen-containing heterocycle or an amine group optionally substitutedwith one or two C₁-C₄ alkyl groups, or b) addition salts of the aboveformula I compound with an acid.
 2. A compound according to claim 1,wherein R₂ and R₃ represent a methyl group at position 2,6 on thearomatic ring.
 3. A method for preparing a formula I compound as definedin claim 1, and its addition salts, comprising: a) allowing an acid offormula:

in which R₁ represents a hydrogen, a halogen, a C₁-C₃ alkyl group, C₁-C₃alkoxy group, R₂ represents a hydrogen, a halogen, C₁-C₃ alkyl groups,C₁-C₃ alkoxy group, or a CF₃ group, R₃ represents a hydrogen, a halogen,C₁-C₃ alkyl group, C₁-C₃ alkoxy group, R₄ represents a hydrogen or aC₁-C₃ alkyl group, R_(a) represents a C₁-C₄ alkyl group, Y represents a—CH₂—CH₂—O—CH₂— group, to react with a nitrogen-containing heterocycleof formula:

in which X represents CH or a nitrogen atom, p represents 2 or 3, Arepresents a single bond, a nitrogen atom optionally substituted with amethyl group (if X does not represent a nitrogen atom), or a straight orbranched C₁-C₅ alkylene group, optionally hydroxylated or of which oneof the carbon atoms is oxidized into a ketone function, B represents anitrogen-containing heterocycle or an amine group optionally substitutedwith one or two C₁-C₄ alkyl groups, on the understanding that, should anon-substituted nitrogen atom be present, this nitrogen atom isprotected by an amino-protecting group, in a solvent, in the presence ofactivators, at a temperature lylng between ambient temperature and theboiling point of the solvent, for about 2 to 15 hours, to obtain theamide of formula:

in which R₁, R₂, R₃, R₄, R_(a), Y, p, X, A and B maintain the samemeaning as in the starting products, b) optionally, removing theamino-protecting groups, and c) optionally, obtaining an addition saltof the formula I compound with a mineral or organic acid.
 4. A methodfor preparing a compound of formula:

in which R₁ represents a hydrogen, a halogen, a C₁-C₃ alkyl group or aC₁-C₃ alkoxy group, R₂ represents a hydrogen, a halogen, a C₁-C₃ alkylgroup or a C₁-C₃ alkoxy group, or a CF₃ group, R₃ represents a hydrogen,a halogen, a C₁-C₃ alkyl group or a C₁-C₃ alkoxy group, R₄ represents ahydrogen, a halogen, a C₁-C₃ alkyl group, R_(a) represents a C₁-C₄ alkylgroup, Y represents a —CH₂—CH₂—O—CH₂— group, X represents CH or anitrogen atom, p represents 2 or 3, A represents a single bond, anitrogen atom optionally substituted with a methyl group, or a straightor branched C₁-C₅ alkylene group optionally hydroxylated or of which oneof the carbon atoms is oxidized into a ketone function, provided that Aand X together do not represent a nitrogen atom, B represents anitrogen-containing heterocycle or an amine group optionally substitutedwith one or two C₁-C₄ alkyl groups, and its addition salts, the methodcomprising: a) allowing an acid of formula:

in which; R₁ represents a hydrogen, a halogen, a C₁-C₃ alkyl group or aC₁-C₃ alkoxy group, R₂ represents a hydrogen, a halogen, a C₁-C₃ alkylgroup or a C₁-C₃ alkoxy group, or a CF₃ group, R₃ represents a hydrogen,a halogen, a C₁-C₃ alkyl group or a C₁-C₃ alkoxy group, R₄ represents ahydrogen or a C₁-C₃ alkyl group, R_(a) represents a C₁-C₄ alkyl group, Yrepresents a —CH₂—CH₂—O—CH₂— group, to react with a chlorination agent,to obtain the acid chloride of formula:

in which R₁, R₂, R₃, R₄, R_(a) and Y have the same meaning as in thestarting compound, and b) allowing the acid chloride of formula IIa toreact with an amine of formula III as defined in claim 3, to obtain thecompound of formula I, and c) optionally, obtaining an addition salt ofthe formula I compound with a mineral or organic acid.
 5. A method forpreparing a formula I compound such as defined in claim 1, and itsaddition salts, comprising: a) allowing an acid compound of formula:

in which Ra represents a C₁-C₄ alkyl group, Y represents a—CH₂—CH₂—O—CH₂— group, and Z_(a) represents an amino-protcting group, toreact with a nitrogen-containing heterocycle of formula:

in which X represents CH or a nitrogen atom, p represents 2 or 3, Arepresents a single bond, a nitrogen atom optionally substituted with amethyl group (if X does not also represent a nitrogen atom) or astraight or branched C₁-C₅ alkylene group, optionally hydroxylated or ofwhich one of the carbon atoms is oxidized into a ketone function, Brepresents a nitrogen-containing heterocycle or an amine groupoptionally substituted with one or two C₁-C₄ alkyl groups, on theunderstanding that, should a non-substituted nitrogen atom be present onsaid nitrogen-containing heterocycle, this nitrogen atom is protected bya different amino-protecting group to the amino-protecting group usedfor acid compound VII, in a solvent, in the presence of activators, at atemperature generally lylng between ambient temperature and the boilingpoint of the solvent, for about 2 to 15 hours, to obtain the amide offormula:

in which Z_(a), R_(a), Y, p, X, A and B maintain the same meaning as inthe starting compounds, b) removing the Z_(a) amino-protecting group toobtain the secondary amine of formula:

in which R_(a), Y, p, X, A and B maintain the same meaning as in thepreceding compound, c) allowing this secondary amine IX to react with abenzenesulphonyl chloride of formula:

in which R₁ represents one atom or group of atoms selected from ahydrogen atom, the halogens, C₁-C₃ alkyl groups, C₁-C₃ alkoxy groups, R₂represents one atom or group of atoms selected from a hydrogen atom, thehalogens, C₁-C₃ alkyl groups, C₁-C₃ alkoxy groups, or CF₃, R₃ representsone atom or group of atoms selected from a hydrogen atom, the halogens,C₁-C₃ alkyl groups, C₁-C₃ alkoxy groups, R₄ represents one atom or groupof atoms selected from a hydrogen atom or C₁-C₃ alkyl groups, in asolvent, in the presence of an aprotic organic base, at a temperaturebetween about 0 and 50° C., for about 1 to 3 hours, to obtain thesulphonamide of formula:

in which R₁, R₂, R₃, R₄, R_(a), Y, p, X, A and B maintain the samemeaning as in the starting compounds, d) optionally, removing theamino-protecting groups, and e) optionally necessary, obtaining anaddition salt of the formula I compound with a mineral or organic acid.6. A therapeutic composition, wherein, in association with at least onephysiologically acceptable excipient, it contains at least one formula Icompound according to claim 1, or one of its pharmaceutically acceptableaddition salts with an acid.
 7. The compound of claim 1, which isselected from the group consisting of:1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]acetyl]-4-[2-(1-pyrrolidinyl)ethyl]piperazine,bis-trifluoroacetate;N-[2-[2-[4-[(3RS)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-N,2,4,6-tetramethylbenzenesulphonamide,bis trifluoro-acetate;N-[2-[2-[4-[(3RS)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide;N-[2-[2-[4-[(3RS)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide;N-[2-[2-[4-v(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate;N-[2-[2-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,4,6-tetramethylbenzenesulphonamide,fumarate;1-[[2-[[(4-methoxy-2,6-dimethylphenyl)suphonyl]methylamino]-ethoxy]-acetyl]-4-[3-(1-pyrrolidinyl)propyl]piperazine,bis-trifluoroacetate;1-[[2-[[(4-methoxy-2,6-dimethylphenyl)suphonyl]methylamino]-ethoxy]-acetyl]-4-[2-(4-morpholinyl)ethyl]piperazine,bis-trifluoroacetate;1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]-acetyl]-4-[2-(4-morpholinyl)ethyl]piperazine,bis-trifluoroacetate;1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-4-[3-(1-piperidinyl)propyl]piperazine,bis-trifluoroacetate;1-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]-acetyl]-4-[3-(dimethylamino)propyl]piperazine,bis-trifluoroacetate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,bis trifluoroacetate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-1-piperazinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide,fumarate;1-(1-azabicyclo[2.2.2]oct-3-yl)hexahydro-4-[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]acetyl]-1H-1,4-diazepine,fumarate;N-[2-[2-[4-[3-(1-azetidinyl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-3-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[(1-methyl-2-imidazolyl)methyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[3-(dimethylamino)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate; N-[2-[2-[4-[3-(1-pyrrolidinyl)propyl]-b1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[3-(1-pyrrolidinyl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(8-cyclopropyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate;N-[2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(1-cyclopropyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-(1-methylethyl)-2,6-dimethylbenzenesulphonamide,difumarate.N-[2-[2-[4-(1-ethyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate;N-[2-[2-[4-[1-(1,1-dimethylethyl)-4-piperidinyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[(1-methyl-4-piperidinyl)methyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate;N-[2-[2-[4-[3-(dimethylamino)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-methoxy-N-methyl-benzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-methoxy-N-methyl-benzenesulphonamide,difumarate;N-[2-[2-[4-[2-(1-methyl-4-piperidinyl)ethyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)hexahydro-1H-1,4-diazepin-1-yl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-(1-methylethyl)-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[1-(1-methylethyl)-4-piperidinyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate;N-[2-[2-[4-[3-(1-piperidinyl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4-dichloro-6-methoxy-N-methyl-benzenesulphonamide,difumarate;N-[2-[2-[4-(1-ethyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-methoxy-N-methyl-benzenesulphonamide,fumarate;N-[2-[2-[4-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-methyl-2,6-dichlorobenzenesulphonamide,fumarate;N-[2-[2-[4-(1,2,2,6,6-pentamethyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,bis(trifluoroacetate);N-[2-[2-[4-[3-(4-methyl-1-piperazinyl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[3-(4-methyl-hexahydro-1H-1,4-diazepin-1-yl)propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[8-(1-methylethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[3-(4-methyl-hexahydro-1H-1,4-diazepin-1-yl)-3-oxo-propyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,bis(trifluoroacetate);N-[2-[2-[4-[2-(4-methyl-hexahydro-1H-1,4-diazepin-1-yl)ethyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,trifumarate;N-[2-[2-[4-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-cyclopropyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N-ethyl-2,6-dimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-fluoro-N-methyl-benzenesulphonamide;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,6-dichloro-4-fluoro-N-methyl-benzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-bromo-2,6-dichloro-N-methyl-benzenesulphonamide;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-bromo-2,6-dichloro-N-methyl-benzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4,6-trichloro-N-methyl-benzenesulphonamide;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4,6-trichloro-N-methyl-benzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4-dichloro-6-methyl-N-methyl-benzenesulphonamide;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-2,4-dichloro-6-methyl-N-methyl-benzenesulphonamide,difumarate;N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-ethoxy]ethyl]-4-methoxy-2,3,6-trimethyl-N-methyl-benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-[3-(4-piperidinyl)-propyl]-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-[3-(1-methyl-4-piperidinyl)propyl]-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(4-piperidinyl)-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide,bis(trifluoroacetate);4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(6-amino-3-pyridinyl)-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(6-amino-3-pyridinyl)-1-piperazinyl]ethoxy]ethyl]benzenesulphonamide,fumarate;N-[2-[2-[4-[2-(dimethylamino)-1,1-dimethylethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,trifluoroacetate;N-[2-[2-[4-[2-(dimethylamino)-1-hydroxyethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,trifluoroacetate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-cyclopropyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[4-(1-methylethyl)-1-piperazinyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-ethyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-cyclopropyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-[2-[2-[4-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethyl-benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-[methyl(1-methylethyl)amino]ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[methyl(1-methyl-4-piperidinyl)amino]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1-(1-methylethyl)-4-piperidinyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-ethyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-cyclopropyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(4-morpholinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(1-azetidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-ethyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-[2-[2-[4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethyl-benzenesulphonamide,fumarate;N-cyclopropyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;2,4-dichloro-N,3-dimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(1-azetidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;2,6-dichloro-4-methoxy-N-methyl-N-[2-[2-[4-[2-(dimethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide,fumarate;2,6-dichloro-4-methoxy-N-methyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(1-pyrrolidinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(4-ethyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-cyclopropyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-[(4-methyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;N-ethyl-4-methoxy-2,6-dimethyl-N-[2-[2-[4-[(4-methyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;N-methyl-4-methoxy-2,6-dichloro-N-[2-[2-[4-[(4-methyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(1-piperidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,trifluoroacetate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-[2-[2-[4-[2-(ethylmethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate;N-[2-[2-[4-[2-(diethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,fumarate;4-methoxy-N-(1-methylethyl)-2,6-dimethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(4-morpholinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-[2-[2-[4-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate;N-[2-[2-[4-[(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,difumarate; 4-methoxy-N-[2-[2-[4-[2-(1-methyl-4-piperidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-N,2,6-trimethylbenzenesulphonamide,fumarate;4-methoxy-N-[2-[2-[4-[2-(1-piperidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-N,2,6-trimethylbenzenesulphonamide,fumarate;4-methoxy-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-N-methyl-2-trifluoromethyl-benzenesulphonamide,trifluoroacetate;4-methoxy-N-[2-[2-[4-[2-(1-methyl-4-piperazinyl)-2-oxoethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-N,2,6-trimethylbenzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[1,1-dimethyl-2-(diethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,trifluoroacetate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(dimethylamino)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(1-azetidinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N,2,4,6-tetramethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,trifluoroacetate;N-methyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]-2-trifluoromethyl-benzenesulphonamide,trifluoroacetate;4-methoxy-N-methyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]-2-trifluoromethyl-benzenesulphonamide,trifluoroacetate;N,2,4,6-tetramethyl-N-[2-[2-[4-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,trifluoroacetate;2,6-dichloro-4-methoxy-N-methyl-N-[2-[2-[4-(1-methyl-4-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(dimethylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]-ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(4-cyclopropyl-1-piperazinyl)-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[4-(1,1-dimethylethyl)-1-piperazinyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(4-methyl-1-piperazinyl)methyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(4-methyl-1-piperazinyl)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(4-morpholinyl)-propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(4-morpholinyl)-propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(1-pyrrolidinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(1-pyrrolidinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(4-methyl-1-piperazinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(4-methyl-1-piperazinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(1-azetidinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(1-azetidinyl)propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(dimethylamino)-propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[3-(dimethylamino)-propyl]-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide,fumarate;N-[2-(2-[4,4′-bipiperidin]-1-yl-2-oxoethoxy)ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide,trifluoroacetate;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(methylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[2-(methylamino)ethyl]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,fumarate;N-[2-[2-(4-amino-1-piperidinyl)-2-oxoethoxy]ethyl]-4-methoxy-N,2,6-trimethylbenzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-1-piperidinyl]-2-oxoethoxy]-ethyl]benzenesulphonamide,bis(trifluoroacetate);4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(methylamino)-1-piperidinyl]-2-oxoethoxy]ethyl]-benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[methyl(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-[methyl(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-1-piperidinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,bis(trifluoroacetate);4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(1-piperazinyl-methyl)-1-piperidinyl]ethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-(1-piperazinyl-methyl)-1-piperidinyl]ethoxy]ethyl]benzenesulphonamide,fumarate;4-methoxy-N,2,6-trimethyl-N-[2-[2-oxo-2-[4-[1-oxo-2-(4-methyl-1-piperazinyl)ethyl]-1-piperidinyl]ethoxy]-ethyl]benzenesulphonamide,bis(trifluoroacetate);4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)]-1-piperazinyl]-2-oxoethoxy]ethyl]benzenesulphonamide;4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)]-1-piperazinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,dihydrochioride; and4-methoxy-N,2,6-trimethyl-N-[2-[2-[4-(1-methyl-4-piperidinyl)]-1-piperazinyl]-2-oxoethoxy]ethyl]benzenesulphonamide,difumarate.
 8. A therapeutic composition comprising a formula I compoundof claim 7 or a salt thereof and a physiologically acceptable excipient.